Derivatives of isoquinoline (and naphthalene) sulfonamides

ABSTRACT

Novel quinoline sulfonamino derivatives having a vessel smooth muscle relaxation activity as well as a platelet agglutination inhibitory activity and inhibitory activity to protein kinase A, myosin light chain kinase, proteinkinase C, and calmodulindependent proteinkinase II, but having little action or cardio function; a process for the production of the derivatives, and a pharmaceutical composition containing the derivative.

This is a divisional of copending application Ser. No. 07/453,623 filedon Dec. 20, 1989, now U.S. Pat. No. 5,081,246.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to compounds having a vessel smooth musclerelaxation activity, a process for the production thereof, and to theuse thereof.

2. Description of the Related Art

Quinoline compounds having a vessel smooth muscle relaxation activityare described in, for example, Japanese Unexamined Patent Publication(KOKAI) Nos. 60-81168, 61-126026, 61-271221, 61-293914, 62-103066, and63-211267; and U.S. Pat. Nos. 4,456,757, 4,525,589, 4,560,755,4,634,770, 4,678,783, 4,709,032, and 4,798,897.

Among the compounds described in the above references, some have asatisfactory smooth muscle relaxation activity, but have problems withrelation to toxicity, organ-specificity, and safety.

SUMMARY OF THE INVENTION

Accordingly, the objects of the present invention are to provide novelcompounds having a satisfactory smooth muscle relaxation activity, and alow toxicity, high organ-specificity, and high safety.

More particularly, the present invention provides a compound representedby the formula (I): ##STR1## wherein Y represents N, H₃ C--N or CH; R₁represents a hydrogen atom, an optionally substituted lower alkyl group,a formyl group, a halophenylpropargyl group, an optionally substitutedaralkyl group or optionally substituted phenyl; and

(1) R₂ represents a group represented by the formula (II): ##STR2##wherein R₃ represents a hydrogen atom, an optionally substituted loweralkyl group, a formyl group, a halophenylpropargyl group, an optionallysubstituted aralkyl group or optionally substituted phenyl; or R₁ and R₃together form a lower alkylene group;

R₄ represents a hydrogen atom or a lower alkyl group;

R₅ represents a hydrogen atom, a halogen atom, a nitro group, a loweralkyl group, an optionally substitute hydroxyl group, an optionallysubstituted N-substituted amino group, an optionally substituted carboxygroup, a polyfluoro-lower alkyl group, a cyano group, a hydroxymethylgroup, a methylthio group, methyl sulfinyl group or methylsulfonylgroup;

R₆ represents a hydrogen atom, a halogen atom or a lower alkoxy group;or

R₅ and R₆ together form a lower alkylenedioxy group;

R₇ represents a hydrogen atom or a lower alkoxy group;

X represents a vinylene group or an ethynylene group;

Ar represents a phenyl group, a naphthyl group or a heterocyclyl group;

m represents an integer of 1 to 3; and

W represents a lower alkylene group, an optionally substituted phenylenegroup or an optionally substituted phenylene-lower alkylene group; or

(2) R₂ represents a group represented by the formula (III): ##STR3##wherein R₁₀ represents a hydrogen atom, a nitro group, an optionallysubstituted amino group, an optionally substituted hydroxyl group, alower alkyl group, or a halogen atom; or R₁ and R₁₀ together form alower alkylene group;

R₁₁ represents a hydrogen atom, a hydroxyl group or a lower alkoxygroup;

R₁₂ and R₁₃ each represent a hydrogen atom, or together represent=0;

Ar has the same meaning as defined under the formula (II);

n represents an integer of 1 to 3; and

A represents the group >CR₁₄ R₁₅ or >NR₁₄ ; wherein R₁₄ represents ahydrogen atom, an optionally substituted hydroxy group, an optionallysubstituted phenyl group, an acyl group, a substituted carbonyl group,an optionally substituted alkoxycarbonyl, a substituted carbamoyl, anoptionally substituted amino group, an arylsulfonyl group, anaralkylsulfonyl group, an aralkyl group, or a heterocyclyl group; and

R₁₅ represents a hydrogen atom or a lower alkoxy group, or R₁₅ and R₁₄together represent an alkylenedioxy group or =0; and

quaternary ammonium salts of the compound of the formula (I), andnontoxic salts of the compound of the formula (I).

The present invention above provides a process for the production of acompound represented by the formula (I) wherein R₂ represents a grouprepresented by the formula (II), comprising the steps of

(1) reacting a compound represented by the formula (IV): ##STR4##

wherein Y, W, R₁ and R₃ have the same meanings as defined above, with acompound represented by the formula (V): ##STR5## wherein B represents--CH₂ Hal or --CO--R₄ , and other symbols have the same meanings asdefined in claim 1; and optionally

(2) reducing a compound produced in the spet (1), and/or optionally

(3) alkylating or formylating a compound produced in the step (1) or(2).

The present invention moreover provides a process for the production ofa compound represented by the formula (I) wherein R₂ represents a grouprepresented by the formula (II), comprising the steps of:

(1) reacting a compound represented by the formula (VI): ##STR6## with acompound represented by the formula (VII): ##STR7## or a reactivederivative thereof or a salt thereof, wherein all the symbols in theformula (VI) and (VII) have the same meanings as defined above, andoptionally,

(2) alkylating a compound produced in the step (1).

The present invention still further provides a process for theproduction of a compound represented by the formula (I), according toclaim 1, wherein R₂ represents a group represented by the formula (III),comprising the steps of:

(1) reacting a compound represented by the formula (VIII). ##STR8## witha compound represented by the formula (VII): ##STR9## or a reactivederivative thereof or a salt thereof, wherein all the symbols in theformulae (VIII) and (VIII) have the some meanings as defined above;

and optionally carrying out one or more than one of the following steps(2) to (8),

(2) hydrolysis to form a free hydroxyl group or an amino group;

(3) deprotection of a protecting group for a hydroxyl or amino group;

(4) acylation or substituted-alkoxy-carbonylation of a hydroxyl group oran amino group;

(5) alkylation of a hydroxyl group or an amino group;

(6) amination or hydroxylation of a carbonyl group;

(7) reduction of a nitro group to an amino group; and

(8) carbonylation of an acetal.

The present invention also provides a pharmaceutical compositioncomprising a compound described above.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the definition of the present invention, the optionally substitutedlower alkyl includes an unsubstituted lower alkyl and a substitutedlower alkyl. "Lower alkyl" means an alkyl containing up to seven carbonatoms, preferably up to four carbon atoms. The unsubstituted lower alkylinclude straight chain lower alkyl and branched chain lower alkyl andare, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, pentyl, hexyl and heptyl.

In the definition of R₁ and R₃ , the substituted lower alkyls include anoptionally substituted amino lower alkyl, such as 2-amino ethyl and3-amino propyl, N,N-dimethyl amino propyl, 4-piperidyl lower alkyl suchas 4-piperidyl propyl, a morpholino lower alkyl such as morpholinoethyl,and piperidino lower alkyl such as piperidinoethyl. Thehalophenylpropargyl includes fluoro- chloro-, brom- andiode-phenylproparyls, and is preferably p-chlorophenylpropargyl. Theoptionally substituted aralkyls include unsubstituted aralkyl, forexample, a phenyl lower alkyl such as benzyl and phenylethyl, and asubstituted phenyl-lower alkyl such as p-methoxybenzyl. The optionallysubstituted phenyl includes a substituted phenyl such as 3,4-dimethoxyphenyl. The alkylene group formed by R₁ and R₃ is, for example, amethylene, ethylene, or propylene group.

The lower alkyl as R₄ is as defined above.

The halogen as R₅ is floro, chloro, bromo or iodo; preferably chloro.

The lower alkyl as R₅ is as defined above.

The optionally substituted hydroxy as R₅ includes a hydroxyl group, anda substituted hydroxyl group, for example, a lower alkoxy such asmethoxy, ethoxy or propoxy.

The optionally N-substituted amino as R₅ is an amino, or a lower alkylamino such as dimethylamino.

The optionally substituted carboxy as R₅ includes a carboxyl group, perse., and a substituted carboxy, for example, a lower alkoxy carbonylsuch as methoxy carbonyl, ethoxycarbonyl, and propoxycarbonyl.

The polyfluoro-lower alkyl as R₅ is, for example, trifluoromethyl.

The halogen as R₆ is as defined above for R₅

The lower alkoxy as R₆ is as defined above for R₅.

The lower alkylenedioxy formed by R₅ and R₆ is, for example,methylenedioxy, 1,2-ethylenedioxy, 1,3-dipropylenedioxy,1,2-dipropylenedioxy, or the like, preferably 1,2-ethylenedioxy.

The lower alkoxy as R₇ is as defined above for R₅.

The lower alkylene group as W is, for example, a methylene group,ethylene group, 1,3-propylene group, or 1,4-butylene group.

The phenylene group as W is, for example, a 1,2-phenylene group or1,3-phenylene. The phenylene lower alkylene group as W is, for example,a 1,2-phenylene- or 1,3-phenylene-lower alkylene group such as1,2-phenylene-ethylene or a 1,3-phenylene-ethylene group. The optionalsubstituent for the phenylene moiety is, for example, a lower alkoxycarbonyl such as methoxy carbonyl.

The heterocyclyl group as Ar is, for example, a pyridyl such as2-pyridyl, 3-pyridyl or 4-pyridyl, a pyridyl such as 2 pyridyl,3-pyridyl or 4-pyridyl, a pyrrolyl such as 2-pyrrolyl or 3-pyrrolyl, athionyl such as 2-thionyl a 3-thionyl, or a furyl such as 2-furyl or3-furyl.

The optionally substituted amino as R₁₀ includes free amino andsubstituted amino. In the substituted amino, the substituents areexemplified by a lower alkyl such as methyl, ethyl, propyl or otherlower alkyl as defined above, and substituted sulfo such as isoquinolinesulfo, naphtharenesulfo, methanesulfo, toluenesulfo. Accordingly, thesubstituted amino is, for example, isoquinoline sulfonamide, N-loweralkyl isoquinolinesulfonamide such as N-methyl-sulfonamide,naphtharenesulfonamide, N-lower alkyl naphtharenesulfonamide such asN-methylnaphtharenesulfonamide, methansulfonamide, N-lower alkylmethansulfonamide, N-methyl methansulfonamide, toluenesulfonamide, orN-lower alkyl methansulfonamide such as N-methyl methanesulfonamide. Thesubstituted amino further is phtharimide.

The substituted hydroxy group as R₁₀ includes ester, ether and protectedhydroxy. The ester is, for example, a substituted sulfonyloxy such asisoquinolinesulfonyloxy, toluenesulfonyloxy or naphtharenesulfonyloxy,or a lower alkanoyloxy such as acetoxy, propionyloxy or butanoyloxy. Theether is, for example, a lower alkoxy such as methoxy, ethoxy orpropoxy; an aralkyloxy such as benzyloxy; a lower alkanoyloxy-loweralkoxy such as acetoxy methoxy; or a heterocycle-lower alkoxy such as2-pyridyl methoxy or 4-pyridylmethoxy.

The lower alkyl as R₁₀ is as defined above. The halogen as R₁₀ is asdefined above. The lower alkoxy as R₁₀ is as defined above for R₅. Thehalogen as R₁₀ is as defined above for R₅. The heterocycle group as Ar₂is, for example, an imidazolyl such as 4-imidazolyl.

The substituted hydroxyl group as R₁₄ is, for example, an ether groupsuch as a lower alkoxy defined as above, or an optionally substitutedaralkyl, for example, phenyl-lower alkyl optionally substituted on thephenyl, such as benzyl, phenylpropyl, 4-methylbenzyl,3,4-dichlorobenzyl, or an ester group, for example, a lower alkanoyloxysuch as acetoxy or propanoyloxy.

The substituted phenyl as R₁₄ is, for example, a lower alkylphenyl forexample 3-methylpheny, a lower alkoxyphenyl such as 2,3- or a4-methoxypheny, mono- or di-holophenyl such as 4-chlorophenyl,3,4-dichlorophenyl.

The acyl as R₁₄ is, for example, an acylphenyl such as benzoyl, on anaralkylcarbonyl such as benzylcarbonyl or phenylpropylcarbony.

The substituted alkoxycarbonyl R₁₄ is, for example, a phenyl-loweralkoxycarbonyl such as benzyloxycarbonyl, or tert-butoxy carbonyl.

The substituted carbonyl is, for example, an arylcarbonyl such asphenylcarbonyl, or an aralkyl carbonyl such as benzylcarbonyl.

The substituted amino R₁₄ is, for example, a lower alkylamino, anoptionally substituted aralkylamine or N,N-lower alkyl aralkylamino, forexample, methylamino benzylamino, 3,4-dichlorobenzylamino, N,N-methylbenzylamino or N,N-methyl 3,4-dichloroamino.

The aryl sulfonyl R₁₄ is, for example, benzylsulfonyl, aisoquinolinesulfonyl.

The aralkylsulfonyl R₁₄ is, for example, benzylsulfonyl or phenylpropylsulfonyl.

The aralkyl R₁₄ is, for example, benzyl or phenylpropionyl.

The heterocyclyl group R₁₄ is, for example, a pyridyl such as 2-pyridyl,or a pyrimidyl such as 2-pyrimidyl.

Since the present compounds have a nitrogen atom they can formquaternary ammonium salts, or salts such as nontoxic salts. To form aquaternary ammonium salt, a compound of the present invention is reactedwith, for example, methyl iodide. The salts of the present invention arepreferably nontoxicic salts, for example, salts with an inorganic acidsuch as hydrochloric acid, sulfuric acid, nitric acid, phosphorus acid,hydrogen bromide, hydrogen iodide or the like, as well as salts with anorganic acid, such as citric acid, acetic acid, oxalic acid, tartaricacid, sulfonic acids such as methane sulfonic acid, ethanesulfonic acidbenzenesulfonic acid, fumaric acid, maleic acid, malic acid or the like.

In an embodiment for the production of the present compounds, a compoundrepresented by the formula (IV) as described above is reacted with acompound represented by the formula (V) as described above.

In a preferable embodiment of this variation, a compound of the formula(IV), wherein R₁ and R₃ represent a hydrogen atom, is reacted, and afterthe reaction, the resulting intermediate is derivatized, for example,alkylated or formulated to introduce R₁ and/or R₃.

In a particular case, an isoquinolinesulfonamide represented by theformula (IV'): ##STR10## is reacted with a compound of the formula (V),and if necessary, the resulting intermediate is reduce. The reaction iscarried out, for example, in a medium such as methanol,dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, diglyme,benzene, at a temperature of 0° C. to 100° C., preferably a roomtemperature. The reduction is carried out using, for example, sodiumborohydride, aluminum lithium hydride or the like, at a temperature of0° C. to 60° C. preferably at a room temperature. The introduction of R₁and/or R₃ can be carried out by using a halide of R₁ and/or R₃, i.e.,Hal-R₁ or Hal-R₂ while removing hydrogen halide. Where an alkylenehalide is used, a compound wherein R₁ and R₃ are linked is provided. Foran introduction of formyl, the intermediate is reacted with formic acidin the presence of acetic anhidride. The above-mentioned reactions arecarried out, for example, in chloroform, dimethylacetamide,dimethylformamide or other aprotic solvent, at a temperature of about 0°C. to 100° C., preferably at a room temperature.

In another embodiment for the production of the present compounds, acompound of the formula (VI) is reacted with a compound (VII). In apreferable embodiment, a compound of the formula (VI) wherein R₃ ishydrogen atom is reacted with a compound of the formula and after thereaction, the resulting intermediate is alkylated to introduce R₃.

In a particular embodiment, a compound of the formula (VI') ##STR11##wherein R₁₆ is an optional substituent on the phenyl moiety W, isreacted with a compound of the formula (VII) to obtain a compoundrepresented by the formula (I-a): ##STR12##

The reaction is carried out in a medium such as pyridine,dimethylformamide, acetonitrile, dioxane, tetrahydrofuran,dichloromethane, chloroform or the like, at a temperature of about 0° C.to 40° C., preferably 20° C. to 30° C.

Note, the product (Ia) is reacted with a compound which introduces thesubstituent R₁ and/or R₃. The compound which introduces R₁ and/or R₃ is,for example, a halogen compound of R₁ or R₃ , i.e., Hal-R₁ or Hal-R₃wherein Hal represents a halogen atom.

The reaction is carried out in a medium such as tetrahydrofuran,dimethylformamide, dioxane, deethoxymethane, methanol, ether such asethyl ether, chloroform, ethyl acetate or the like in the pressure of abase which kinds the resulting hydrogen halide during the reaction, forexample a tertiary amine such as pyridine, dimethylaminopyridine.N-methylpiperidine or triethylamine, or an inorganic base such aspotassium bicarbonate, potassium hydroxide, sodium carbonate, sodiumhydroxide or the like.

The starting material (VI) wherein R₃ is a hydrogen atom can be obtainedby reacting a compound represented by the formula (VIII): ##STR13## witha compound represented by the formula (IX):

    H.sub.2 N--W--NH.sub.2                                     (IX).

For example, to obtain the intermediate (VI'), a compound of the formula(VIII'): ##STR14## with a compound of the formula (IX'): ##STR15##

These reactions can be carried out under substantially the samecondition as for the introduction of R₁ and R₃.

In another embodiment for the production of the sent compound (I), acompound of the formula (VIII) is reacted with a compound of the formula(VII).

The starting material (VIII) can be obtained by reacting a compoundrepresented by the formula (X): ##STR16## wherein R₁₇ is a hydrogen atomor a lower alkyl, with a compound represented by the formula (XI):##STR17##

By this reaction, the compound (VIII) wherein R₁₂ and R₁₃ together form═O is obtained. A reduction of this compound provides the compound(VIII) wherein both R₁₂ and R₁₃ represent a hydrogen atom.

In a particular embodiment, a known compound tyrosine having the aminogroup protected, and represented by the formula (Xa): ##STR18## isreacted with pyperazine having the nitrogen atom protected isrepresented by the formula (XIa): ##STR19## to obtain an intermediaterepresented by the formula (VIIIa): ##STR20##

Next, the intermediate (VIIIa) is then condensed withisoquinolinesulfonylchloride to obtain a compound represented by theformula (XII): ##STR21##

Next, the following modification of the compound (XII) can be carriedout to obtain some of the present compounds:

(2a) Hydrolysis to remove the isoquinolinesulfonyl group to free hydroxyon the phenyl ring;

(3a) Deprotection of the piperazine ring;

(4a) Acylation or alkylation of the free hydroxy;

(4a) Acylation of the nitrogen atom of the piperazine moiety;

(5a) Alkylation of the sulfonamide group.

To prepare other compounds of the present invention, bistidine,phenylalanine or the like can be used in place of tyrosine, and/orpiperidine or the like can be used in place of piperazine. Moreover, anN-alkylated compound can be used in place of an N-protected compound(IIa), and/or a hydroxy-protected compound of the compound (IIa) can beused. The compound (VIIIa) or (XII) can be reduced to convert thecarbonyl structure to the methylene chain. The orth portion of thephenyl ring can be linked with an amino group via an alkylene chain toform a ring structure. Where piperidine is used in place of piperazine,the piperidine moiety can be converted to a corresponding moiety havingan acetal structure at the fourth position thereof. After condensationwith a sulfonic acid derivative, (8a) the acetal can be carbonylated,(6a) the carbonyl can be converted to hydroxy or an amino group, (4b)the hydroxyl or amino group can be acylated, or (5b) the hydroxyl oramino group can be alkylated, to obtain some of the desired compounds ofthe present invention.

The reaction of the compound (X) and (XI) is carried out in a mediumsuch as tetrahydrofuran, dioxane, dichloromethane, or other aproticsolvent at a temperature of about 0° C. to 40° C., preferably 20° C. to30° C.

The reaction of the compound (VII) and the compound (VIII) is carriedout in an aprotic solvent such as tetrahydrofuran, methylene chloride,chloroform, dimethylformamide, or the like in the presence of a hosesuch as triethylamine or the like at a temperature of about 0° C. to 40°C., preferably 20° C. to 30° C.

The hydrolysis of step (2) is carried out in a solvent such as methanol,tetrahydrofuran, a mixture thereof, dimethyl-sulfoxide or the like, inthe presence of a base such as sodium hydroxide, potassium hydroxide orthe like.

The reprotection of step (3) is carried out in a solvent such asmethanol, ethanol, chloroform, ethyl acetate or the like.

The acylation of step (4) is carried out in a solvent such aschloroform, tetrahydrofuran, pyridine or the like, in the presence of abase such as triethylamine.

The alkylation of step (5) is carried out in a solvent such asdimethylformamide, tetrahydrofuran, ethyl acetate, methanol, methylenechloride, or a mixture thereof.

The hydroxylation of step (6) is carried out in a protonic solvent suchas methanol or ethanol in the presence of a reducing agent such assodium borohydride, sodium cyanoborohydride. The amination of step (6)is carried out, after an imine formation, under the same condition asfor the hydroxylation. The reduction of nitro in step (7) is carried outin a solvent, for example, an alcohol such as methanol or ethanol, bycatalytic hydrogenation using as a catalyst a noble methanol catalystsuch as palladium on carbon.

The conversion of acetol to oxo is carried out by acidic hydrolysis inan aqueous solution.

EXAMPLES

The present invention will now be further illustrated by, but is by nomeans limited to, the following example.

In the examples, melting points were determined by a melting pointmeasurement apparatus Yamato MP-21 (Yamato Kagaku, Japan) using acapillary; nuclear magnetic resonance spectra (¹ H-NMR) were determinedby JEOL.JNM-FX200 (Nippon Denshi, Japan); molecular weights weredetermined by JMS-D300 type mass spectrometer (Nippon Denshi, Japan);and infrared absorption spectra (IR) were determined by IRA-1 (NipponBunko Kogyo, Japan).

REFERENCE EXAMPLE 1 1-N-(Benzyloxycarbonyl) histidyl]-4-phenylpiperazine

7.13 g of N,N'-dibenzyloxycarbonyl histidine, 3.00 g of4-phenylpiperazine and 16.1 g of N-hydroxybenzotriazole were dissolvedin 100 ml of tetrahydrofuran, and to the mixture was added 3.84 g of DCC(dicyclohexylcarbodiimide), and the whole was stirred at a roomtemperature for three hours. An insoluble matter was filtered off, thefiltrate was concentrated under a reduced pressure, and to theconcentrate was added 200 ml of ethyl acetate to reform crystals, whichwere then filtered off. The filtrate was sequentially washed with 20%potassium carbonate aqueous solution and saturated sodium chlorideaqueous solution, dried over magnesium sulfate, and concentrated under areduced pressure. The resulting residue was dissolved in 60 ml ofmethanol, and after an addition of a 10% ammonium-methanol solution andstirring at a room temperature for 30 minutes, the solution wasconcentrated under a reduced pressure to obtain a residue, which wasthen subjected to silica gel chromatography and eluted withchloroform/methanol (50:1 to 10:1) to obtain 6.61 g of the titlecompound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 2.81-3.20 (6H, m), 3.40-3.82 (4H, m), 4.95 (1H,m), 5.09 (2H, s), 5.78 (1H, d, J=8.3 Hz), 6.80-6.97 (4H, m), 7.20-7.30(2H, m), 7.34 (5H, s), 7.55 (1H, s).

REFERENCE EXAMPLE 2 1-[N-(tert-Butoxycarbonyl)histidyl]-4-phenylpiperazine

6.61 g of 1-[N-(benzyloxycarbonyl)histidyl]-4-phenylpiperazine wasdissolved in 80 ml of methanol, and to the solution was added 4 g of 5%palladium on carbon catalyst with ice cooling, and the mixture wasstirred under a hydrogen atmosphere at a room temperature for 20 hours,and filtered to obtain a filtrate, which was then concentrated under areduced pressure to obtain 4.26 g of a residue. The residue wasdissolved in 80 ml of dimethylformamide, and to the solution weresequentially added 6.8 g of tert-butoxycarboxylic acid anhydride and 10ml of triethylamine, and the mixture was stirred at a room temperaturefor 90 minutes. 200 ml of ethyl acetate was added to the reactionmixture, which was then washed twice with saturated sodium chlorideaqueous solution, dried over magnesium sulfate, and filtered to obtain afiltrate. The filtrate was concentrated under a reduced pressure toobtain a residue, which was then dissolved in 100 ml of methanol, and tothe resulting solution was added 20 ml of 10% sodium hydroxide aqueoussolution, and the whole was stirred at a room temperature for 30minutes. The reaction mixture was concentrated under a reduced pressureto one third of the original volume, and after the addition of 150 ml ofwater, the concentrate was extracted twice with 80 ml each ofchloroform, the resulting chloroform phase was dried over magnesiumsulfate, filtered, and concentrated under a reduced pressure to obtain aresidue. The residue was applied on a silica gel column, and eluted withchloroform/methanol (50:1 to 20:1) to obtain 4.53 g of the titlecompound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.43 (9H, s), 2.80-3.22 (6H, m), 3.40-3.83 (4H,m), 4.87 (1H, m), 5.46 (1H, br), 6.86-6.93 (4H, m), 7.23-7.31 (2H, m),7.57 (1H, s).

REFERENCE EXAMPLE 31-[2-(tert-Butoxycarbonylamino)-3-imidazol-4(5)-yl-propyl]-4-phenylpiperazine

A solution of 1.3 g of lithium aluminum hydride in 38 ml oftetrahydrofuran was added to a solution of 4.56 g of aluminum chloridein 38 ml of ethyl ether with ice cooling, and the mixture was stirredfor 20 minutes with ice cooling. To the mixture was dropwise added asolution of 4.53 g of1-[N-(tert-butoxycarbonyl)histidyl]-4-phenylpiperazine in 51 ml oftetrahydrofuran, and stirring for one hour with ice cooling, to thereaction mixture was added 20 ml of 25% potassium carbonate aqueoussolution, followed by 100 ml of chloroform to obtain a suspension. Thesuspension was filtered using silica as a filter aid to obtain afiltrate. After the silica was washed with 20% methanol in chloroform,the combined filtrate was concentrated under a reduced pressure toobtain a residue. The residue was applied to a silica gel column, andeluted with chloroform/methanol (40:1 to 10:1) to obtain 3.1 g of thetitle compound in a colorless amorphous.

H-NMR (CDCl₃, δ ppm): 1.44 (9H, s), 2.33 (1H, dd, J=7.3, 12.2 Hz), 2.47(1H, dd, J=7.8, 12.2 Hz), 2.64 (4H, m), 2.93 (2H, m), 3.20 (4H, m), 3.97(1H, m), 5.10 (1H, br), 6.81-6.97 (4H, m), 7.21-7.30 (2H, m), 7.58 (1H,s).

EXAMPLE 1N-{1-[1-(5-Isocuinolinesulfonyl)imidazol-4(5)-yl-methyl]-2-(4-phenylpiperazinyl)ethyl}-5-isoquinolinesulfonamide

3.1 g of the amorphous compound obtained in Reference Example 3 wasdissolved in 10 ml of ethyl acetate, and to the solution was added 16 mlof 4N hydrochloric acid in ethyl acetate was added, and the mixture wasstirred at a room temperature for 30 hours and evaporated to drynessunder a reduced pressure. To the residue were added 70 ml oftetrahydrofuran and 30 ml of chloroform to form a suspension, to whichwere added 6 g of isoquinolinesulfonic acid chloride and 30 ml oftriethylamine, and after stirring at a room temperature for 18 hours,150 ml of water was added and the whole was extracted twice with 70 mlof chloroform. The extract was dried over magnesium sulfate andconcentrated under a reduced pressure to obtain a residue, which wasthen applied to silica gel column, and eluted with chloroform/methanol(80:1 to 60:1) to obtain 1.86 g of the title compound in a colorlessamorphous form.

IR (KBr) cm⁻¹ : 1618, 1600, 1490, 1380, 1325, 1210, 1170, 1132, 1073;

¹ H-NMR (CDCl₃, δ ppm): 2.00-2.34 (6H, m), 2.59-2.81 (6H, m), 3.39 (1H,m), 6.74-6.89 (3H, m), 7.04 (1H, d, J=1.5 Hz), 7.19-7.29 (3H, m), 7.69(1H, t, J=7.3 Hz), 7.80 (1H, t, J=1.5 Hz), 8.21 (1H, d, J=8.3 Hz), 8.34(1H, d, J=8.3 Hz), 8.38-8.46 (3H, m), 8.52 (1H, dd, J=1.0, 7.3 Hz), 8.69(1H, d, J=6.3 Hz), 8.77 (1H, d, J=6.3 Hz), 9.36 (1H, s), 9.39 (1H, s).

EXAMPLE 2N-[1-(Imidazol-4(5)-yl-methyl)-2-(4-phenylpiperazinyl)ethyl]-5-isoquinolinesulfonamide

250 mg of the amorphous compound obtained in Example 1 was dissolved ina mixture of 1 ml of tetrahydrofuran and 5 ml of methanol, and to thesolution 1 ml of 4N sodium hydroxide was added. After stirring at a roomtemperature for 10 minutes, 20 ml of water was added to the mixture,which was then extracted twice with a mixture of 10 ml of chloroform and2 ml of isopropanol. The extract was dried over magnesium sulfate, andconcentrated under a reduced pressure to obtain a residue, which wasthen applied to a silica gel column, and eluted with chloroform/methanol(20:1) and chloroform/methanol/triethylamine (20:1:0.2) to obtain 163 mgof the title compound in a colorless amorphous form.

IR (KBr) cm⁻¹ : 1615, 1600, 1490, 1448, 1320, 1225, 1153, 1130;

¹ H-NMR (CDCl₃, δ ppm): 2.06-2.44 (6H, m), 2.67-2.90 (5H, m), 3.02 (1H,dd, J=5.4, 10.0 Hz), 3.25 (1H, m), 6.74-6.90 (4H, m), 7.19-7.33 (2H, m),7.54 (1H, s), 7.74 (1H, t, J=7.8 Hz), 8.24 (1H, d, J=7.8 Hz), 8.47 (1H,d, J=6.4 Hz), 8.52 (1H, dd, J=1.0, 7.32 Hz), 8.70 (1H, d, J=5.9 Hz),9.38 (1H, s).

EXAMPLE 3 N-{1-[1-(5-Isoquinolinesulfonyl)imidazol-4(5)-yl-methyl]-2-(phenylpiperazinylethyl}-N-methyl-5-isoquinoline sulfonamide

1.45 g of the amorphous compound obtained in Example 1 was dissolved in20 ml of dimethylformamide, and to the solution were sequentially added120 mg of 60% sodium hydride and 0.2 ml of methyl iodide with icecooling, and after stirring for 30 minutes with ice cooling, and 30 mlof water was added. After extraction of the reaction mixture with 30 mlof ethyl acetate, the extract was washed with saturated sodium chlorideaqueous solution, dried over magnesium sulfate and concentrated under areduced pressure to obtain a residue, which was then applied to a silicagel column and eluted with chloroform/methanol (80:1) to obtain 616 mgof the title compound in a colorless amorphous form.

IR (KBr) cm⁻¹ : 1618, 1600, 1490, 1380, 1320, 1210, 1170, 1140, 1080;

¹ H-NMR (CDCl₃, δ ppm): 2.35-2.47 (6H, m), 2.64 (1H, dd, J=7.8, 14.6Hz), 2.80 (3H, s), 2.85-2.97 (5H, m), 4.36 (1H, m), 6.82-6.89 (3H, m),7.08 (1H, d, J=1.5 Hz), 7.21-7.29 (2H, m), 7.61 (1H, t, J=7.3 Hz), 7.75(1H, t, J=7.8 Hz), 7.87 (1H, d, J=1.5 Hz), 8.14 (1H, d, J=7.8 Hz),8.25-8.29 (2H, m), 8.37-8.45 (3H, m), 8.64 (1H, d, J=5.9 Hz), 8.76 (1H,d, J=6.3 Hz), 9.31 (1H, s), 9.35 (1H, s).

EXAMPLE 4 N-[1-(Imidazol-4(5)-yl-methyl)-2-(4-phenylpiperazinyl)ethyl]-N-methyl-5-isoquinoline sulfonamide

450 mg of the amorphous compound obtained in Example 3 was dissolved ina mixture of 2 ml of tetrahydrofuran and 10 ml of methanol, and to thesolution was added 1 ml of 4 N sodium hydroxide. After stirring at aroom temperature for 10 minutes, the reaction mixture was worked upaccording to the same procedure as described in Example 2 to obtain 299mg of the title compound in a colorless amorphous form.

IR (KBr) cm⁻¹ : 1595, 1490, 1448, 1320, 1225, 1150, 1128;

¹ H-NMR (CDCl₃, δ ppm): 2.45-2.65 (6H, m), 2.89 (3H, s), 2.90-3.08 (6H,m), 4.37 (1H, m), 6.68 (1H, s), 6.82-6.90 (3H, m), 7.20-7.32 (3H, m),7.64 (1H, t, J=7.8 Hz), 8.14 (1H, d, J=7.8 Hz), 8.31 (1H, d, J=6.3 Hz),8.46 (1H, dd, J=1.0, 7.3 Hz), 8.62 (1H, d, J=5.9 Hz), 9.29 (1H, s).

REFERENCE EXAMPLE 4 N-(tert-Butoxycarbonyl)-3,4-dibenzyloxyphenylalaninebenzyl ester

21.12 g of N-(tert-butoxycarbonyl) DOPA was dissolved in 200 ml ofdimethylformamide, and after 50 g of benzyl bromide and 40 g ofpotassium carbonate were added, the mixture was stirred at a roomtemperature for 40 hours. After the addition of 400 ml of sodiumchloride aqueous solution, the reaction mixture was extracted with 500ml of ethyl acetate, and the extract was washed twice with saturatedsodium chloride aqueous solution, dried over magnesium sulfate,filtered, and concentrated under a reduced pressure. To the resultingresidue was added hexane to crystallize the title compound, which wasthen washed, filtered and dried to obtain 30.0 g of the colorlesscrystals.

¹ H-NMR (CDCl₃, δ ppm): 1.42 (9H, s), 2.99 (2H, d, J=14.14 Hz), 4.59(1H, m), 4.98 (1H, brd), 5.05 (2H, s), 5.07 (2H, s), 5.11 (2H, s), 6.56(1H, dd, J=2.0, 7.8 Hz), 6.71 (1H, d, J=2.0 Hz), 6.79 (1H, d, J=7.8 Hz),7.20-7.50.

REFERENCE EXAMPLE 5 N-(tert-Butoxycarbonyl)-3,4-dibenzyloxyphenylalanine

30.0 g of the crystals obtained in Example 4 was dissolved in 600 ml ofmethanol, and after the addition of 65 ml of 10% sodium hydroxide, themixture was stirred at a room temperature for 20 hours, and 1000 ml ofwater was added. The reaction mixture was adjusted to pH 4 withconcentrated hydrochloric acid, and extracted twice with 800 ml ofchloroform. The extract was dried over magnesium sulfate andconcentrated under a reduced pressure to crystallize the title compound,which was then filtered and washed with hexane to obtain 25.2 g ofcolorless crystals.

¹ H-NMR (CDCl₃, δ ppm): 1.40 (9H, s), 3.02 (2H, m), 4.49 (1H, brs), 4.88(1H, brs), 5.11 (4H, s), 6.68 (1H, dd, J=2.0, 7.8 Hz), 6.76 (1H, d,J=2.0 Hz), 6.74 (1H, d, J=7.8 Hz), 7.23-7.45 (10H, m).

REFERENCE EXAMPLE 61-[N-(tert-Butoxycarbonyl)-3,4-dibenzyloxyphenylalaninyl]-4-phenylpiperazine

5.67 g of the crystals obtained in Reference Example 5, 1.9 g ofN-phenylpiperazine and 1.53 g of N-hydroxybenzotriazole were dissolvedin 80 ml of methylene chloride, and after the addition of 2.4 g of DCC,the mixture was stirred at a room temperature for 18 hours. Resultinginsoluble matter was filtered off, and washed with ethyl acetate.

The combined filtrate was concentrated under a reduced pressure toobtain a residue, which was then applied to a silica gel column, andeluted with hexane/ethyl acetate (2:1) to obtain 6.39 g of the titlecompound as colorless amorphous.

¹ H-NMR (CDCl₃, δ ppm): 1.44 (9H, s), 2.39 (1H, m), 2.76-3.10 (6H, m),3.30 (1H, m), 3.61 (2H, m), 4.78 (1H, m), 5.03 (2H, s), 5.14 (2H, s),5.42 (1H, brd, J=8.3 Hz), 6.69 (1H, dd, J=2.0, 8.3 Hz), 6.79-6.91 (5H,m), 7.20-7.48 (12H, m).

REFERENCE EXAMPLE 71-{2-[N-(tert-Butoxycarbonylamino)]-3-(3,4-dibenzyloxyphenyl)propyl}-4-phenylpiperazine

3.66 g of the colorless amorphous obtained in Reference Example 6 wasdissolved in 50 ml of tetrahydrofuran, and the addition of 700 mg oflithium aluminum hydride with ice cooling, the mixture was stirred for90 minutes with ice cooling, and to the mixture was added water untilfoaming ended. Then 80 ml of chloroform was added to the reactionmixture to form a suspension, which was then filtered using silica gelas a filter acid to remove insoluble matter. The resulting filtrate wasconcentrated under a reduced pressure to obtain a residue, which wasthen applied to a silica gel column, and eluted with hexane/ethylacetate (3:1) to obtain 2.67 g of the title compound in colorlessamorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.43 (9H, s), 2.24 (2H, m), 2.53 (4H, m), 2.79(2H, m), 3.16 (4H, m), 3.90 (1H, m), 4.58 (1H, brs), 5.13 (2H, s), 5.16(2H, s}, 6.70 (1H, dd, J=2.0, 8.3 Hz), 6.80-6.93 (5H, m), 7.20-7.46(12H, m).

REFERENCE EXAMPLE 81-[2-Amino-3-(3,4-dibenzyloxyphenyl)propyl]-4-phenylpiperazine

4.35 g of the amorphous compound obtained in Reference Example 7 wasdissolved in 20 ml of ethyl acetate, and after the addition of 30 ml of4 N hydrochloric acid in ethyl acetate, the mixture was stirred at aroom temperature for one hour. The reaction mixture was concentratedunder a reduced pressure, alkalized with sodium bicarbonate aqueoussolution, and extracted twice with 80 ml of chloroform, and the extractwas dried over magnesium sulfate and concentrated under a reducedpressure. The resulting residue was applied to a silica gel column andeluted with chloroform-methanol (100:1 to 30:1) to obtain 1.64 g of thetitle compound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 2.27-2.68 (8H, m), 3.10-3.20 (5H, m), 5.10 (2H,brs), 5.14 (2H, s), 5.17 (2H, s), 6.73 (1H, dd, J=2.0, 8.3 Hz),6.81-6.94 (5H, m), 7.22-7.46 (12H, m).

EXAMPLE 5N-{1-[3,4-Dibenzyloxyphenyl)methyl]-2-(4-phenylpiperazinyl)ethyl)-5-isoquinolinesulfonamide

640 mg of the amorphous compound obtained in Reference Example 8 wasdissolved in 15 ml of methylene chloride, and to the solution were added1 ml of triethylamine and 350 mg of 5-isoquinolinesulfonyl chloride withice cooling, and after stirring for one hour with ice cooling, was added50 ml of water, and the mixture was extracted twice with 50 ml ofchloroform. The extract was dried over magnesium sulfate andconcentrated under a reduced pressure to obtain a residue, which wasthen applied to a silica gel column and eluted with hexane/ethyl acetate(1:1) to obtain 470 mg of the title compound in a colorless amorphousform.

¹ H-NMR (CDCl₃, δ ppm): 2.08-2.24 (6H, m), 2.64-2.91 (6H, m), 3.30 (1H,m), 5.08 (2H, s), 5.10 (2H, s), 6.51 (1H, dd, J=2.0, 8.3 Hz), 6.63 (1H,d, J=2.0 Hz), 6.71 (1H, d, J=8.3 Hz), 6.76-6.89 (3H, m), 7.21-7.43 (12H,m), 7.67 (1H, t, J=7.8 Hz), 8.18 (1H, d, J=8.3 Hz), 8.44 (2H, m), 8.67(1H, d, J=5.9 Hz), 9.34 (1H, s).

EXAMPLE 6N-{1-[(3,4-Dibenzyloxyphenyl)methyl]-2-(4-phenylpiperazinyl)ethyl}-N-methyl-5-isoquinolinesulfonamide

470 mg of the amorphous compound obtained in Example 5 was dissolved in8 ml of dimethylformamide, and to the solution were sequentially added30 mg of 60% sodium hydride and 0.1 ml of methyl iodide with icecooling, and after stirring for two hours with ice cooling was addedsaturated sodium chloride, and the mixture was extracted with 50 ml ofethyl acetate. The extract was washed with saturated sodium chlorideaqueous solution, dried over magnesium sulfate and concentrated under areduced pressure to obtain a residue, which was then applied to a silicagel column and eluted with hexane/ethyl acetate (1:1) to obtain 413 mgof the title compound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 2.34 (1H, dd, J=6.35, 13.2 Hz), 2.42-2.60 (5H,m), 2.65 (1H, dd, J=7.3, 14.2 Hz), 2.81 (1H, dd, J=6.4, 14.2 Hz), 2.86(3H, s), 2.99 (4H, m), 4.22 (1H, m), 5.03 (2H, s), 5.10 (2H, s), 6.54(1H, dd, J=2.0, 8.3 Hz), 6.61 (1H, d, J=2.0 Hz), 6.63 (1H, d, J=8.3 Hz),6.82-6.90 (3H, m), 7.19-7.53 (13H, m), 8.05 (1H, d, J=8.3 Hz), 8.24 (1H,dd, J=1.0, 7.3 Hz), 8.30 (1H, d, J=5.9 Hz), 8.60 (1H, d, J=5.9 Hz), 9.24(1H, d, J=1.0 Hz).

EXAMPLE 7 N-{1-[(3,4-Dihydroxyphenyl)methyl]-2-(1-phenylpiperazinylethyl}-N-methyl-isoquinoline sulfonamide

310 mg of the amorphous compound obtained in Example 6 was dissolved in2 ml of 1,2-ethanedithiol, and to the solution were added 1 ml of borontrifluoride/ethyl ether, and after stirring at a room temperature for 18hours, was added saturated sodium bicarbonate aqueous solution, and thereaction mixture was extracted twice with a mixture of chloroform andmethanol (10:1). The extract was dried over magnesium sulfate, andconcentrated under a reduced pressure to obtain a residue, which wasapplied to a silica gel column and eluted with chloroform/methanol (80:1to 20:1) to obtain 148 mg of the title compound in a colorless amorphousform.

IR (KBr) cm⁻¹ : 1600, 1495, 1448, 1328, 1230, 1155, 1130;

¹ H-NMR (CDCl₃, δ ppm): 2.41 (1H, dd, J=10.25, 14.65 Hz), 2.50-2.98 (7H,m), 3.01 (3H, s), 3.17 (4H, m), 4.06 (1H, m), 6.12 (1H, dd, J=20, 8.3Hz), 6.20 (1H, d, J=8.3 Hz), 6.28 (1H, d, J=2.0 Hz), 6.82-6.95 (3H, m),7.26 (2H, m), 7.62 (1H, t, J=7.8 Hz), 8.09 (1H, d, J=6.8 Hz), 8.13 (1H,d, J=9.3 Hz), 8.30 (1H, d, J=6.8 Hz), 8.41 (1H, d, J=4.9 Hz), 9.25 (1H,s).

EXAMPLE 8N-{1-[(3,4-Dihydroxyphenyl)methyl]-2-(4-phenylpiperazinyl)ethyl}-5-isoquinolinesulfonamide

The amorphous compound obtained in Example 5 was treated according tothe procedure as described in Example 7 to obtain the title compound incolorless amorphous form.

IR (KBr) cm⁻¹ : 1610, 1600, 1490, 1445, 1320, 1220, 1150, 1128;

¹ H-NMR (CDCl₃, δ ppm): 2.30-2.60 (6H, m), 2.74-3.02 (6H, m), 3.36 (1H,m), 6.15 (1H, d, J=8.3 Hz), 6.33 (1H, d, J=8.3 Hz), 6.36 (1H, s),6.76-6.90 (3H, m), 7.19-7.29 (2H, m), 7.65 (1H, t, J=7.8 Hz), 8.16 (1H,d, J=8.3 Hz), 8.33 (1H, d, J=6.5 Hz), 8.39 (1H, d, J=7.3 Hz), 8.51 (1H,d, J=5.5 Hz), 9.28 (1H, s).

REFERENCE EXAMPLE 96,7-Dibenzyloxy-3-[4-phenylpiperazinyl)methyl]-1,2,3,4-tetrahydroisoquinoline

1.00 g of the amorphous compound obtained in Reference Example 8 wasdissolved in 2 ml of tetrahydrofuran, and to the solution was added 0.25ml of 37% formalin. After stirring at a room temperature for 30 minutes,600 mg of 12 N hydrochloric acid was added to the mixture, which wasthen stirred at a room temperature for two hours. After the addition ofsaturated sodium bicarbonate aqueous solution, the reaction mixture wasextracted twice with 20 ml of chloroform. The extract was dried overmagnesium sulfate, and concentrated under a reduced pressure to obtain aresidue, which was then applied to a silica gel column and eluted withchloroform/methanol (100:1) to obtain 585 mg of the title compound in acolorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 2.28-2.38 (8H, m), 3.02 (1H, m), 3.21 (4H, m),3.95 (2H, s), 5.11 (4H, s), 6.63 (1H, s), 6.68 (1H, s), 6.80-6.95 (3H,m), 7.20-7.46 (12H, m).

EXAMPLE 96,7-Dibenzyloxy-2-(5-isoquinolinesulfonyl)-3-[(4-phenylpiperazinyl)methyl]-1,2,3,4-tetrahydroisoquinoline

580 mg of the amorphous compound obtained in Reference Example 9 wasdissolved in 10 ml of methylene chloride, and to the solution were added1 ml of triethylamine and 400 mg of 5-isoquinoline sulfonyl chloride.HClwith ice cooling. The mixture was stirred at a room temperature for twohours, and after the addition of 20 ml of water, extracted twice with 10ml of chloroform. The extract was dried over magnesium sulfate andconcentrated under reduced pressure to obtain a residue, which was thenapplied to a silica gel column and eluted with hexane/ethyl acetate(1:1) to obtain 610 mg of the title compound in a colorless amorphousform.

¹ H-NMR (CDCl₃, δ ppm): 2.31 (1H, dd, J=7.8, 11.6 Hz), 2.43 (1H, dd,J=6.8, 11.6 Hz), 2.53 (4H, m), 2.70 (1H, dd, J=2.0, 16.2 Hz), 2.87 (1H,dd, J=4.2, 16.2 Hz), 3.05 (4H, m), 4.26 (1H, d, J=15.6 Hz), 4.48 (1H, d,J=15.6 Hz), 4.49 (1H, m), 5.06 (2H, s), 5.07 (2H, s), 6.56 (1H, s), 6.60(1H, s), 6.80-6.90 (3H, m), 7.20-7.95 (12H, m), 7.64 (1H, t, J=7.8 Hz),8.15 (1H, d, J=7.81 Hz), 8.37 (1H, d, J=5.9 Hz), 8.48 (1H, dd, J=1.0,7.3 Hz), 8.64 (1H, d, J=6.4 Hz), 9.30 (1H, d, J=1.0 Hz).

EXAMPLE 106,7-Dihydroxy-2-(5-isoquinolinesulfonyl)-3-[(4-phenylpiperazinyl)methyl]-1,2,3,4-tetrahydroisoquinoline

To 314 mg of the amorphous compound obtained in Example 9, were added 2ml of 1,2-ethanedithiol and 1 ml of boron trifluoride/ethyl ether, andthe mixture was stirred at a room temperature for 18 hours. After theaddition of saturated sodium bicarbonate aqueous solution, the reactionmixture was extracted twice with a mixture of chloroform and methanol(1:1), and the extract was dried over magnesium sulfate and concentratedunder a reduced pressure to obtain a residue, which was then applied toa silica gel column and eluted with chloroform/methanol (50:1 to 20:1)to obtain 213 mg of the title compound in a colorless amorphous form.

IR (KBr) cm⁻¹ : 1610, 1600, 1490, 1445, 1320, 1225, 1150, 1130;

¹ H-NMR (CDCl₃, δ ppm): 2.35-2.80 (8H, m), 3.11 (4H, m), 4.24 (1H, d,J=16.1 Hz), 4.40 (1H, d, J=16.1 Hz), 4.55 (1H, m), 6.45 (2H, s),6.80-6.90 (3H, m), 7.20-7.28 (2H, m), 7.67 (1H, t, J=7.8 Hz), 8.14 (1H,d, J=8.5 Hz), 8.40 (1H, d, J=6.3 Hz), 8.50 (1H, dd, J=1.0, 7.3 Hz), 8.59(1H, d, J=6.4 Hz), 9.25 (1H, d, J=1.0 Hz).

REFERENCE EXAMPLE 101-[N-(tert-Butoxycarbonyl)-p-nitrophenylalanyl]-4-phenylpiperazine

7.03 g of p-nitrophenylalanine was suspended in 70 ml of 1,4-dioxane,and to the suspension were added 28 ml of 10% sodium hydroxide aqueoussolution and 7.5 g of di-tert-butyl-dicarbonate, and the mixture wasstirred at a room temperature for 30 minutes. 200 ml of water and 7 mlof 12 N hydrochloric acid were added to the reaction mixture, which wasthen extracted with 150 ml of ethyl acetate, and the extract was washedwith saturated sodium chloride aqueous solution, dried over magnesiumsulfate, and concentrated under a reduced pressure. The resultingresidue was dissolved in 150 ml of tetrahydrofuran, and to the solutionwere added 6.0 g of N-phenylpiperazine and 5.5 g ofN-hydroxybenzotriazole, and further added 7.6 g of DCC. After stirringat a room temperature for three hours, the reaction mixture was filteredto remove insoluble matter and the filtrate was concentrated under areduced pressure, and the resulting residue was dissolved in 200 ml ofethyl acetate. The solution was sequentially washed with 10% potassiumcarbonate aqueous solution and saturated sodium chloride aqueoussolution, dried over magnesium sulfate, and concentrated under a reducedpressure to obtain a residue, which was then applied to a silicon gelcolumn and eluted with hexane/ethyl acetate (2:1) to obtain 11.1 g ofthe title compound as pale yellow crystals.

¹ H-NMR (CDCl₃, δ ppm): 1.40 (9H, s), 2.83-3.20 (6H, m), 3.37 (1H, m),3.57-3.70 (3H, m), 3.84 (1H, m), 4.92 (1H, m), 5.40 (1H, d, J=8.3 Hz),6.85-6.95 (3H, m), 7.24-7.32 (2H, m), 7.38 (2H, d, J=8.8 Hz), 8.16 (2H,d, J=8.8 Hz).

EXAMPLE 111-[N-(5-Isoquinolinesulfonyl)-p-nitrophenylalanyl]-4-phenylpiperazine

11.0 g of the crystals obtained in Reference Example 10 was dissolved in100 ml of ethyl acetate, and after the addition of 100 ml of 4 Nhydrochloric acid in ethyl acetate, the reaction mixture was stirred ata room temperature for one hour and concentrated to dryness under areduced pressure. To the residue was added 200 ml of saturated sodiumbicarbonate, and the mixture was extracted twice with 100 ml ofchloroform. The extract was dried over magnesium sulfate andconcentrated under a reduced pressure to obtain a residue, which wasthen applied to a silica gel column and eluted with chloroform/methanol(80:1 to 10:1) to obtain free amine. The free amine was dissolved in 100ml of methylene chloride, and to the solution were sequentially added8.5 g of 5-isoquinoline sulfonyl chloride.HCl and 20 ml oftriethylamine. The reaction mixture was stirred at a room temperaturefor 18 hours, and after the addition of water, extracted twice with 100ml of chloroform. The extract was dried over magnesium sulfate andconcentrated under a reduced pressure to obtain a residue, which wasthen applied to a silica gel column and eluted with chloroform/methanol(100:1 to 50:1) to obtain 9.66 g of the title compound as colorlesscrystals.

Melting point: 184°-188° C. (decomposed);

IR (KBr) cm⁻¹ : 1660, 1600, 1520, 1420, 1345, 1325, 1230, 1150, 1135;

¹ H-NMR (CDCl₃, δ ppm}: 2.72-- 3.06 (6H, m), 3.20-3.61 (4H, m), 4.46(1H, m), 6.06 (1H, br), 6.83 (2H, d, J=7.8 Hz), 6.94 (1H, t, J=7.3 Hz),7.10 (2H, t, J=8.8 Hz), 7.29 (2H, m), 7.56 (1H, t, J=7.8 Hz), 7.82 (2H,d, J=8.8 Hz), 8.09 (1H, d, J=7.8 Hz), 8.22-8.29 (2H, m), 8.71 (1H, d,J=6.3 Hz), 9.26 (1H, s).

EXAMPLE 121-[N-(5-Isoquinolinesulfonyl)-N-methyl-p-nitrophenylalanyl]-4-phenylpiperazine

5.87 g of the crystals obtained in Example 11 was dissolved in 60 ml ofdimethylformamide, and to the solution were sequentially added 500 mg of60% sodium hydride and 1.5 ml of methyl iodide with ice cooling. Afterstirring for two hours with ice cooling, water was added to the reactionmixture, which was then extracted with 150 ml of ethyl acetate. Theextract was washed with saturated sodium chloride aqueous solution,dried over magnesium sulfate and concentrated under a reduced pressureto obtain a residue, which was applied to a silica gel column and elutedwith chloroform/methanol (100:1) to obtain 5.93 g of the title compoundin a yellow amorphous form.

IR (KBr) cm⁻¹ : 1640, 1600, 1535, 1445, 1340, 1225, 1150, 1125;

¹ H-NMR (CDCl₃, δ ppm): 2.60 (1H, dd, J=4.9, 12.7 Hz), 2.83 (1H, m),2.92-3.06 (3H, m), 3.06 (3H, s), 3.40 (1H, dd, J=7.8, 13.2 Hz),3.46-3.63 (2H, m), 3.70-3.88 (2H, m), 5.23 (1H, dd, J=4.9, 9.8 Hz), 6.82(2H, d, J=7.8 Hz), 6.91 (1H, t, J=7.3 Hz), 7.22-7.30 (4H, m), 7.73 (1H,t, J=7.8 Hz), 8.07 (2H, d, J=8.8 Hz), 8.25 (1H, d, J'1.0, 7.3 Hz), 8.48(1H, d, J=6.4 Hz), 8.71 (1H, d, J=6.4 Hz), 9.37 (1H, d, J=1.0 Hz).

EXAMPLE 13 1-[p-Amino-N-(5-isoquinolinesulfonyl)-N-methylalanyl]-4-phenylpiperazine

6.08 g of the amorphous compound obtained in Example 12 was dissolved in70 ml of methanol, and to the solution were added 5 ml of 12 Nhydrochloric acid and 30 ml of water, and then 5 g of 5% palladium oncarbon. The mixture was stirred at a room temperature under a hydrogenatmosphere for 30 minutes, and filtered to remove insoluble matter, andthe filtrate was concentrated under a reduced pressure, and to theresidue was added 150 ml of saturated sodium bicarbonate aqueoussolution, and the mixture was extracted twice with 200 ml of chloroform.The extract was dried over magnesium sulfate and concentrated under areduced pressure to obtain a residue, which was then applied to a silicagel column and eluted with chloroform/methanol (50:1) to obtain 3.32 gof the title compound in a yellow amorphous form.

IR (KBr) cm⁻¹ : 1635, 1600, 1495, 1445, 1325, 1220, 1150, 1125;

¹ H-NMR (CDCl₃, δ ppm): 2.47-2.56 (2H, m}, 2.87-3.22 (4H, m), 3.14 (3H,s), 3.33-3.75 (4H, m), 5.14 (1H, dd, J=4.9, 9.8 Hz), 6.50 (2H, d, J=8.3Hz), 6.80-6.92 (5H, m), 7.22-7.34 (2H, m), 7.69 (1H, t, J=7.8 Hz), 8.20(1H, d, J=8.3 Hz), 8.36 (1H, dd, J=1.5, 7.3 Hz), 8.40 (1H, d, J=5.9 Hz),8.68 (1H, d, J=6.4 Hz), 9.34 (1H, s).

EXAMPLE 14

3.75 g of the crystal prepared in Example 11 was treated according tothe procedure as described in Example 13 to obtain 2.17 g of1-[p-amino-N-(5-isoquinolinesulfonyl)phenylalanyl]-4-phenylpiperazine asyellow crystals.

IR (KBr) cm⁻¹ : 1635, 1600, 1495, 1440, 1320, 1225, 1155, 1135;

¹ H-NMR (CDCl₃, δ ppm): 2.41 (1H, m), 2.59-3.07 (6H, m), 3.17 (1H, m),3.33 (1H, m), 3.51 (1H, m), 4.35 (1H, m), 5.95 (1H, d, J=9.3 Hz), 6.38(2H, d, J=8.3 Hz), 6.75 (2H, d, J=8.3 Hz), 6.78 (2H, d, J=7.8 Hz), 6.91(1H, t, J=7.3 Hz), 7.22-7.30 (2H, m), 7.60 (1H, t, J=8.3 Hz), 8.12 (1H,d, J=8.3 Hz), 8.30-8.35 (2H, m), 8.71 (1H, d, J=5.9 Hz), 9.30 (1H, s).

EXAMPLE 15

1-[N-(5-Isoquinolinesulfonyl)-p-(p-toluenesulfonylamino)phenylalanyl]-4-phenylpiperazine

200 mg of the crystals obtained in Example 14 was dissolved in 5 ml ofpyridine, and to the solution was added 90 mg ofp-toluenesulfonylchloride with ice cooling, and the mixture was stirredfor one hour with ice cooling and poured to 30 ml of saturated sodiumbicarbonate aqueous solution. The mixture was extracted twice with 15 mlof chloroform, and the extract was dried over magnesium sulfate andconcentrated under a reduced pressure to obtain a residue, which wasthen applied to a silica gel column and eluted with chloroform/methanol(80:1 to 50:1) to obtain 128 mg of the title compound.

IR (KBr) cm⁻¹ : 1635, 1600, 1335, 1225, 1155, 1090;

¹ H-NMR (CDCl₃, δ ppm): 2.30 (3H, s), 2.65-2.80 (4H, m), 2.83-3.04 (2H,m), 3.17-3.50 (4H, m), 4.33 (1H, m), 6.14 (1H, d, J=9.3 Hz), 6.70-6.83(6H, m), 6.93 (1H, t, J=7.3 Hz), 6.77 (1H, s), 7.17 (2H, d, J=8.3 Hz),7.26-7.36 (2H, m}, 7.59 (1H, t, J=7.3 Hz), 7.59 (2H, d, J=8.3 Hz), 8.13(1H, d, J=7.8 Hz), 8.30 (2H, m), 8.64 (1H, br), 9.31 (1H, br).

EXAMPLE 16

The same procedure as described in Example 15 was repeated, except that200 mg of 5-isoquinolinesulfonyl chloride.HCl and 300 mg of the crystalsobtained in Example 14 were used and elution was carried out withchloroform/methanol (40:1 to 20:1), to obtain 372 mg of1-[N-(5-isoquinolinesulfonyl)-p-(5-isoquinolinesulfonylamino)phenylalanyl]-4-phenylpiperazine.

IR (KBr) cm⁻¹ : 1630, 1600, 1340, 1225, 1155, 1135;

¹ H-NMR (CDCl₃, δ ppm): 2.35-3.07 (9H, m), 3.30 (1H, m), 4.26 (1H, m),6.67-6.84 (6H, m), 6.89-6.96 (2H, m), 7.23 (2H, t, J=8.8 Hz), 7.52 (1H,t, J=7.8 Hz), 7.54 (1H, t, J=7.8 Hz), 7.98 (1H, d, J=7.8 Hz), 8.07 (1H,d, J=8.3 Hz), 8.25 (1H, d, J=6.8 Hz), 8.31-8.36 (2H, m), 8.54 (1H, d,J=6.3 Hz), 8.65 (2H, d, J=6.4 Hz), 9.17 (1H, s), 9.26 (1H, s), 10.06(1H, s).

EXAMPLE 17

The same procedure as described in Example 15 was repeated, except that200 mg of 1-naphtharenesulfonyl chloride and 360 mg of the crystalsobtained in Example 14 were used as starting materials and elution wascarried out using chloroform/methanol (80:1 to 50:1), to obtain 385 mgof1-[N-(5-isoquinolinesulfonyl)-p-(1naphtharenesulfonylamino)phenylalanyl]-4-phenylpiperazine.

¹ H-NMR (CDCl₃, δ ppm): 2.40-2.74 (6H, m), 2.80-3.04 (3H, m) 3.33 (1H,m), 4.24 (1H, m), 6.68-6.82 (6H, m), 6.92 (1H, t, J=7.3 Hz), 7.12 (1H,d, J=9.3 Hz), 7.26-7.57 (5H, m), 7.65 (1H, m), 7.78 (1H, d, J=8.3 Hz),7.88 (1H, d, J=7.8 Hz), 7.99 (1H, d, J=8.3 Hz), 8.16 (1H, dd, J=J=1.0,7.3 Hz), 8.36 (1H, d, J=5.9 Hz), 8.65 (1H, d, J=6.4 Hz), 8.77 (1H, d,J=8.8 Hz), 9.22 (1H, s), 9.88 (1H, s).

EXAMPLE 18

The same procedure as described in Example 15 was repeated, except that0.07 ml of methanesulfonyl chloride and 360 mg of the crystals obtainedin Example 14 were used as starting materials and elution was carriedout using chloroform/methanol (50:1 to 30:1), to obtain 356 mg of1-[N-(5-isoquinolinesulfonyl)-p-(methanesulfonylamino)phenylalanyl]-4-phenylpiperazine.

IR (KBr) cm⁻¹ : 1635, 1600, 1330, 1225, 1150;

¹ H-NMR (CDCl₃, δ ppm): 2.38 (1H, m), 2.72 (3H, s), 2.70-2.90 (6H, m),3.04-3.21 (3H, m), 3.42 (1H, m), 4.39 (1H, m), 6.78 (2H, d, J=7.8 Hz),6.88 (1H, t, J=7.3 Hz), 6.92 (2H, d, J=8.3 Hz), 7.00 (2H, d, J=8.3 Hz),7.20-7.30 (3H, m), 7.62 (1H, t, J=7.8 Hz), 8.16 (1H, d, J=8.3 Hz), 8.32(1H, dd, J=1.0, 7.3 Hz), 8.42 (1H, d, J=5.9 Hz), 8.69 (1H, d, J=6.4 Hz),9.15 (1H, s), 9.31 (1H, s).

EXAMPLE 191-[N-(5-Isoquinolinesulfonyl)-p-methanesulfonylamino-N-methylphenylalanyl]-4-phenylpiperazine

700 mg of the amorphous compound obtained in Example 13 was dissolved in7 ml of pyridine, and to the solution was added 0.13 ml ofmethanesulfonyl chloride with ice cooling, and the mixture was stirredfor one hour with ice cooling and poured to 50 ml of saturated sodiumbicarbonate aqueous solution. The mixture was extracted twice with 30 mlof chloroform. The extract was dried over magnesium sulfate andconcentrated under a reduced pressure. The resulting residue was appliedto a silica gel column and eluted with chloroform/methanol (100:1 to50:1) to obtain 790 mg of the title compound.

IR (KBr) cm⁻¹ : 1635, 1595, 1325, 1220, 1145;

¹ H-NMR (CDCl₃, δ ppm): 2.48-2.59 (2H, m), 2.83 (3H, s), 2.85-3.10 (3H,m), 3.12 (3H, s), 3.22 (1H, dd, J=9.8, 13.2 Hz), 3.44-3.80 (4H, m), 5.16(1H,

dd, J=5.4, 9.8 Hz), 6.80-6.93 (4H, m), 7.04 (4H, s), 7.26 (2H, t, J=8.3Hz), 7.72 (1H, t, J=7.8 Hz), 8.23 (1H, d, J=8.3 Hz), 8.35 (1H, dd,J=1.0, 7.3 Hz) 8.42 (1H, d, J=5.9 Hz), 8.68 (1H, d, J=5.9 Hz), 9.36 (1H,s).

EXAMPLE 20

The same procedure as described in Example 19 was repeated, except that360 mg of 1-naphtharenesulfonyl chloride and 700 mg of the amorphouscompound obtained in Example 13 were used as starting materials, andelution was carried out using chloroform/methanol (100:1) to obtain 770mg of1-[N-(5-isoquinolinesulfonyl)-N-methyl-p-(1-naphtharenesulfonylamino)phenylalanyl]-4-phenylpiperazine.

IR (KBr) cm⁻¹ : 1635, 1595, 1440, 1330, 1220, 1150, 1120;

¹ H-NMR (CDCl₃, δ ppm): 2.42 (1H, dd, J=4.9, 12.7 Hz), 2.63 (1H, m),2.85-3.17 (4H, m), 3.07 (3H, s), 3.32-3.73 (4H, m), 5.04 (1H, dd, J=5.4,10.3 Hz), 6.73-6.96 (7H, m), 7.05 (1H, br), 7.30-7.41 (3H, m) 7.54-7.70(3H, m], 7.88 (1H, d, J=7.8 Hz), 7.95 (1H, d, J=8.3 Hz), 8.12 (1H, dd,J=1.0, 7.3 Hz), 8.16 (1H, d, J=8.3 Hz), 8.27 (1H, dd, J=1.5, 7.3 Hz),8.37 (1H, d, J=6.3 Hz), 8.62-8.68 (2H, m), 9.32 (1H, s).

EXAMPLE 21

The same procedure as described in Example 19 was repeated except that320 mg of 5-isoquinolinesulfonyl chloride.HCL as a sulfonating agent,500 mg of the amorphous compound obtained in Example 13, 5 ml ofpyridine and chloroform/methanol (80:1 to 50:1) as an eluent were used,to obtain 498 mg of1-[N-(5-isoquinolinesulfonyl-p-(5-isoquinolinesulfonylamino)-N-methylphenylalanyl]-4-phenylpiperazine.

IR (KBr) cm⁻¹ : 1640, 1595, 1330, 1225, 1155, 1135

¹ H-NMR (CDCl₃, δ ppm): 2.44 (1H, dd, J=4.9, 13.2 Hz), 2.61 (1H, m),2.85-3.26 (5H, m), 3.05 (3H, s), 3.40-3.70 (3H, m), 5.06 (1H, dd, J=4.9,9.8 Hz), 6.77 (2H, d, J=8.8 Hz), 6.79-6.97 (5H, m), 7.31 (2H, t, J=7.3Hz), 7.53 (1H, t, J=8.3 Hz), 7.63 (1H, t, J=8.8 Hz), 8.08 (1H, d, J=8.3Hz), 8.20 (1H, d, J 8.3 Hz), 8.27-8.32 (2H, m), 8.37 (2H, d, J=6.4 Hz),8.64 (1H, d, J=6.4 Hz), 8.67 (1H, d, J=6.4 Hz), 9.29 (1H, s), 9.34 (1H,s)

EXAMPLE 22

The same procedure as described in Example 19 was repeated except that300 mg of p-toluenesulfonyl chloride as a sulfonating agent, 700 mg ofthe amorphous compound obtained in Example 13, 10 ml of pyridine as aneluate and chloroform/methanol (100:1) were used, to obtain 812 mg of1-[N-(5-isoquinolinesulfonyl)-N-methyl-p-(p-toluenesulfonylamino)phenylalanyl]-4-phenylpiperazine

IR (KBr) cm⁻¹ : 1635, 1595, 1440, 1325, 1220, 1150;

¹ H-NMR (CDCl₃, δ ppm): 2.32 (3H, s), 2.50 (1H, dd, J=4.9, 12.7 Hz),2.68 (1H, m), 2.90-3.03 (4H, m), 3.10 (3H, s), 3.29 (1H, m), 3.42-3.73(3H, m), 5.12 (1H, dd, J=5.4, 9.8 Hz), 6.79-6.97 (7H, m), 7.17 (2H, d,J=8.3 Hz), 7.28 (2H, t, J=7.3 Hz), 7.61 (2H, d, J=8.3 Hz), 7.69 (1H, t,J=7.8 Hz), 8.21 (1H, d, J=8.3 Hz), 8.31 (1H, dd, J=1.5, 7.3 Hz), 8.40(1H, d, J=5.9 Hz), 8.65 (1H, d, J=6.4 Hz), 9.35 (1H, s).

EXAMPLE 23 1-{(N-(5-Isoquinolinesulfonyl)-p-N'-(5-isoquinolinesulfonyl)-N'-methylamino]-N-methylphenylalanyl}-4-phenylpiperazine

306 mg of the product in Example 21 was dissolved in 5 ml ofdimethylformamide, and to the solution were added 25 mg of 60% sodiumhydride and 0.1 ml of hydrogen iodide with ice cooling, and the mixturewas stirred for one hour with ice cooling. After the addition of 30 mlof saturated sodium chloride, the mixture was extracted with 30 ml ofethyl acetate, and the extract was washed with saturated sodium chlorideaqueous solution, dried over magnesium sulfate and concentrated under areduced pressure. The resulting residue was applied to a silica gelcolumn and eluted with chloroform/methanol (80:1) to obtain 266 mg ofthe title compound.

IR (KBr) cm⁻¹ : 1640, 1600, 1445, 1340, 1225, 1150, 1130;

¹ H-NMR (CDCl₃, δ ppm): 2.41-2.61 (2H, m), 2.83-3.09 (3H, m), 3.07 (6H,s), 3.27 (1H, dd, J=10.7, 13.2 Hz), 3.43 (1H, m), 3.56-3.71 (3H, m) 5.18(1H, dd, J=4.4, 10.7 Hz), 6.80-6.91 (3H, m), 6.94 (2H, d, J=8.8 Hz),7.00 (2H, d, J=8.8 Hz), 7.21-7.30 (2H, m), 7.60 (1H, t, J=7.8 Hz), 7.73(1H, t, J=7.8 Hz), 7.98 (1H, d, J=5.9 Hz), 8.14-8.23 (3H, m), 8.36 (1H,d, J=8.4 Hz), 8.40 (1H, d, J=5.9 Hz), 8.46 (1H, d, J=6.4 Hz), 8.69 (1H,d, J=6.4 Hz), 9.29 (1H, s), 9.37 (1H, s).

EXAMPLE 24

The same procedure as described in Example 23 was repeated except that594 mg of the product of Example 19 was dissolved in 6 ml ofdimethylformamide and to the solution were added 60 mg of 60% sodiumhydride and 0.1 ml of methyl iodide, to obtain 450 mg of1-[N-(5-isoquinolinesulfonyl)-p-(N'-methanesulfonyl-N'-methylamino)N-methylphenylalanyl]-4-phenylpiperazine.

IR (KBr) cm⁻¹ : 1635, 1595, 1445, 1335, 1225, 1150, 1140;

¹ H-NMR (CDCl₃, δ ppm): 2.36 (1H, m), 2.50 (1H, dd, J=3.9, 12.2 Hz),2.64 (3H, s), 2.81 (1H, m), 2.96-3.16 (2H, m), 3.11 (3H, s), 3.16 (3H,s), 3.31 (1H, dd, J=10.7, 12.7 Hz), 3.37-3.62 (3H, m), 3.78 (1H, m),5.20 (1H, dd, J=4.4, 10.7 Hz), 6.80 (2H, d, J=7.8 Hz], 6.88 (1H, t,J=7.3 Hz), 7.12 (2H, d, J=8.8 Hz), 7.21-7.31 (4H, m), 7.74 (1H, t, J=7.8Hz), 8.24 (1H, d, J=7.8 Hz), 8.38 (1H, dd, J=1.0, 7.3 Hz), 8.47 (1H, d,J=6.4 Hz), 8.71 (1H, d, J=6.4 Hz), 9.37 (1H, s).

EXAMPLE 25

The same procedure as described in Example 23 was repeated, except that587 mg of the product of Example 20 was dissolved in 6 ml ofdimethylformamide and to the solution were added 50 mg of 60% sodiumhydride and 0.1 ml of methyl iodide, and elution was carried out usingchloroform/methanol (100:1), to obtain 490 mg of1-{N-(5-isoquinolinesulfonyl)-N-methyl-p-[N'-methyl-N'-(1-naphtharenesulfonyl)amino]phenylalanyl}-4-phenylpiperazine.

IR (KBr) cm⁻¹ : 1640, 1600, 1440, 1330, 1220, 1150, 1125;

¹ H-NMR (CDCl₃, δ ppm): 2.47 (1H, dd, J=4.4, 12.7 Hz), 2.53 (1H, m),2.80-3.07 (3H, m), 3.07 (3H, s), 3.08 (3H, s), 3.27 (1H, dd, J=10.3,12.7 Hz), 3.38 (1H, m), 3.51-3.65 (3H, m), 5.17 (1H, dd, J=4.4, 10.3Hz), 6.81 (2H, d, J=8.8 Hz), 6.88 (1H, t, J=7.3 Hz), 6.98 (4H, s), 7.24(2H, dd, J=7.3, 8.8Hz), 7.38-7.57 (3H, m), 7.72 (1H, d, J=7.3 Hz), 7.88(1H, d, J=7.8 Hz), 8.01 (1H, d, J=8.3 Hz), 8.04 (1H, d, J=7.3 Hz), 8.23(1H, d, J= 8.3 Hz), 8.32-8.37 (2H, m), 8.46 (1H, d, J=5.9 Hz), 8.68 (1H,d, J=6.3 Hz), 9.36 (1H, s).

EXAMPLE 26

The same procedure as described in Example 23 was repeated, except that650 mg of the product of Example 22 was dissolved in 10 ml ofdimethylformamide, and to the solution were added 60 mg of 60% sodiumhydride and 0.1 ml of methyl iodide, and elution was carried out usingchloroform/methanol (100:1), to obtain 603 mg of1-{N-(5-isoquinolinesulfonyl)-N-methyl-p-[N'-methyl-N'-(p-toluenesulfonyl)amino]phenylalanyl}-4-phenylpiperazine.

IR (KBr) cm⁻¹ : 1640, 1600, 1440, 1335, 1220, 1145;

¹ H-NMR (CDCl₃, δ ppm): 2.37 (3H, s), 2.52 (1H, dd, J=4.9, 12.7 Hz),2.55 (1H, m), 2.80-3.10 (3H, m), 2.99 (3H, s), 3.11 (3H, s), 3.28 (1H,dd, J=10.3, 12.7 Hz), 3.40 (1H, m), 3.50-3.68 (3H, m), 5.20 (1H, dd,J=4.9, 10.3 Hz), 6.81 (2H, d, J=8.3 Hz), 6.88 (1H, t, J=7.3 Hz), 6.98(2H, d, J=8.8 Hz) 7.05 (2H, d, J=8.8 Hz), 7.18 (2H, d, J=8.3 Hz), 7.24(2H, dd, J=7.3, 8.3 Hz), 7.37 (2H, d, J=8.3 Hz), 7.73 (1H, t, J=7.8 Hz),8.23 (1H, d, J=8.3 Hz), 8.36 (1H, dd, J=1.0, 7.8 Hz), 8.46 (1H, d, J=6.4Hz), 8.70 (1H, d, J=6.4 Hz) 9.36 (1H, s).

REFERENCE EXAMPLE 111-(N-Benzyloxycarbonyltyrosyl)-4-(tert-butoxycarbonyl)piperazine

21.31 g of N-benzyloxycarbonyltyrosine and 11.79 ofN-(tert-butoxycarbonyl)piperazine were dissolved in a mixed solvent of200 ml of methylene chloride and 100 ml of ethyl acetate, and to thesolution was added 14 g of DCC. After stirring at a room temperature for40 hours, precipitated insoluble matter was filtered off, and thefiltrate was concentrated under a reduced pressure, and resultingresidue was applied to a silica gel column and eluted with hexane/ethylacetate (1:1) to obtain 23.9 g of the title compound in a colorlessamorphous form

¹ H-NMR (CDCl₃, δ ppm): 1.45 (9H, s), 2.80-3.02 (4H, m), 3.14-3.39 (4H,m), 3.49 (2H, m), 4.83 (1H, m), 5.08 (1H, d., J=12 Hz), 5.10 (1H, d,J=12 Hz), 5.69 (1H, d, J=8.8 Hz), 6.17 (1H, br), 6.72 (2H, d, J=8.8 Hz),7.01 (2H, d,J=8.3 Hz), 7.34 (5H, s).

EXAMPLE 27 1-[N,O-bis(5-isoquinolinesulfonyl)tyrosyl]1-4-(tert-butoxycarbonyl)piperazine

1.00 g of the amorphous compound obtained in Reference Example 11 wasdissolved in 20 ml of methanol, to the solution was added 500 mg of 5%palladium on carbon, and the mixture was stirred under a hydrogenatmosphere at a room temperature for 5 hours. After removing insolublematter by filtration, the filtrate was concentrated under a reducedpressure. To the resulting residue were added sequentially 30 ml oftetrahydrofuran, 630 mg of 5-isoquinolinesulfonyl chloride.HCl and 1.4ml of triethylamine, and the mixture was stirred at a room temperaturefor 50 hours, and after the addition of 100 ml of water, extracted twicewith 50 ml of chloroform. The extract was dried over magnesium sulfateand concentrated under a reduced pressure. The resulting residue wasthen applied to a silica gel column and eluted with chloroform/methanol(50:1 to 25:1) to obtain 1.38 g of the title compound in a yellowamorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.45 (9H, s), 2.53-3.18 (10H, m), 4.29 (1H, m),6.05 (1H, d, J=9.3 Hz), 6.61 (2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.8 Hz),7.62 (1H, t, J=7.8 Hz), 7.66 (1H, t, J=7.8 Hz), 8.19 (2H, d, J=7.8 Hz),8.26-8.31 (3H, m), 8.52 (1H, d, J=5.9 Hz), 8.69 (1H, d, J=5.9 Hz), 8.84(1H, d, J=6.4 Hz), 9.33 (1H, s), 9.43 (1H, s)

EXAMPLE 28 1-[N,O-bis(5-isoquinolinesulfonyl) tyrosyl]piperazine

366 mg of the amorphous compound prepared in Example 27 was dissolved in3 ml of chloroform, and to the solution was added 5 ml of 3Nhydrochloric acid/ethyl acetate. After stirring at a room temperaturefor one hour, the mixture was concentrated under a reduced pressure, andto resulting residue was added 50 ml of saturated sodium bicarbonateaqueous solution. The mixture was then twice extracted with 30 ml of amixed solvent of chloroform/methanol (5:1), and the extract was driedover magnesium sulfate and concentrated under a reduced pressure toobtain 301 mg of a crude preparation of the title compound in acolorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 2.11 (1H, m), 2.35 (1H, m), 2.43 (2H, m),2.70-2.83 (4H, m), 2.90 (1H, m), 3.09 (1H, m), 4.30 (1H, t, J=7.4 Hz),6.65 (2H, d, J=8.3 Hz), 6.88 (2H, d, J=8.3 Hz), 7.62 (1H, dd, J=7.3, 8.3Hz), 7.64 (1H, t, J=7.8 Hz), 8.17 (1H, d, J=8.3 Hz), 8.24-8.31 (4H, m),8.52 (1H, d, J=5.9 Hz), 8.68 (1H, d, J=6.3 Hz), 8.83 (1H, d, J=6.4 Hz),9.32 (1H, s), 9.43 (1H, s).

EXAMPLE 291-Benzyloxycarbonyl-4-N-(5-isoquinolinesulfonyl)tyrosyl]piperazine

620 mg of the crude product obtained in Example 28 was dissolved in 10ml of methylene chloride, and to the solution were sequentially added0.29 ml of benzyloxycarbonyl chloride and 3.04 ml of triethylamine withice cooling. After stirring for two hours with ice cooling, 40 ml ofsaturated sodium chloride aqueous solution was added to the reactionmixture, which was then extracted twice with 20 ml of chloroform, andthe extract was dried over magnesium sulfate and concentrated under areduced pressure to obtain a residue. The residue was dissolved in 6 mlof methanol, and after the addition of 2 ml of 1N sodium hydroxideaqueous solution, the mixture was refluxed for two hours, dried overmagnesium sulfate and concentrated under a reduced pressure. Theresulting residue was applied to a silica gel column and eluted withchloroform/methanol (80:1 to 50:1) to obtain 336 mg of the titlecompound as colorless crystals.

Melting point: 137°-141° C.

IR (KBr) cm⁻¹ : 1700, 1630, 1510, 1417, 1318, 1218, 1148, 1128;

¹ H-NMR(CDCl₃ --CD₃ OD, δ ppm): 2.60-2.77 (2H, m), 2.80-3.55 (8H, m),4.25 (1H, t, J=7.8 Hz), 5.10 (1H, s), 5.12 (1H, s), 6.29, 6.74 (Total2H, each d, each J=8.3 Hz), 6.60, 7.01 (Total 2H, each d, each J=8.3Hz), 7.35 (5H, s), 7.60 (1H, t, J=7.8 Hz), 8.15 (1H, d, J=8.3 Hz), 8.26(1H, d, J=7.8 Hz), 8.29 (1H, d, J=5.9 Hz), 8.57 (1H, d, J=5.9 Hz), 9.25(1H, s).

EXAMPLE 30

The same procedure as described in Example 29 was repeated to obtain1-[N-(5-isoquinolinesulfonyl)tyrosyl]-4-phenylacetylpiperazine in ayellow amorphous form.

IR (KBr) cm⁻¹ : 1620, 1510, 1435, 1320, 1228, 1152, 1130;

¹ H-NMR (DMSO-d₆, δ ppm): 2.20-3.45 (10H, m), 3.67, 370 (Total 2H, eachs), 4.32, 4.82 (Total 1H, each m), 6.45, 6.65 (Total 2H, each d, eachJ=8.3 Hz), 6.82, 7.00 (Total 2H, each d, each J=8.3 Hz), 7.13-7.39 (5H,m), 7.60-7.74 (1H, m), 8.13-8.42 (3H, m), 8.64 (1H, d, J=5.9 Hz), 9.18(1H, br), 9.39 (1H, br).

EXAMPLE 31

The same procedure as described in Example 29 was repeated to obtain1-[N-(5-isoquinolinesulfonyl)tyrosyl]-4-(3-phenylpropionyl)piperazine ascolorless crystals.

Melting point: 172°-178° C.;

IR (KBr) cm⁻¹ : 1630, 1510, 1440, 1320, 1225, 1150, 1128;

¹ H-NMR (CDCl₃ --CD₃ OD, δ ppm): 2.50-3.47 (14H, m), 4.26 (1H, t, J=7.3Hz), 6.32 (2H, d, J=8.3 Hz), 6.62 (2H, d, J=8.3 Hz), 7.15-7.34 (5H, m),7.62 (1H, t, J=7.8 Hz), 8.17 (1H, d, J=7.8 Hz), 8.24-8.33 (2H, m), 8.58(1H, d, J=5.4 Hz), 9.26 (1H, s).

EXAMPLE 32 1-[N,O-bis(5-isoquinolinesulphonyl)tyrosyl]-4-(3-phenylpropyl)piperazine

301 mg of the crude product obtained in Example 28 and 95 mg of3-phenylpropyl bromide were dissolved in 5 ml of dimethylformamide, andto the solution were added 66 mg of potassium carbonate and 72 mg ofsodium iodide. After stirring at 80° C. for 7 hours, 30 ml of saturatedsodium chloride was added to the reaction mixture, which was thenextracted with 40 ml of ethyl acetate, and the extract was washed with30 ml of saturated sodium chloride aqueous solution, dried overmagnesium sulfate, and concentrated under a reduced pressure. Theresulting residue was applied to a silica gel column and eluted withchloroform/methanol (40:1) to obtain 216 mg of the title compound in ayellow amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.60-1.95 (6H, m), 2.06-2.29 (2H, m), 2.53-3.20(8H, m), 4.28 (1H, m), 5.98 (1H, d, J=9.3 Hz), 6.64 (2H, d, J=8.3 Hz),6.86 (2H, d, J=8.3 Hz], 7.14-7.35 (5H, m), 7.59 (1H, t, J=7.8 Hz), 7.62(1H, t, J=7.8 Hz), 8.12 (1H, d, J=8.3 Hz), 8.23-8.29 (4H, m), 8.52 (1H,d, J=5.9 Hz), 8.68 (1H, d, J=6.4 Hz), 8.82 (1H, d, J=6.4 Hz), 9.28 (1H,s), 9.42 (1H, s).

EXAMPLE 33 1-[N-(5-Isoquinolinesulfonyl)tyrosyl]-4-(3-phenylpropyl)piperazine

216 mg of the amorphous compound obtained in Example 32 was dissolved in3 ml of methanol, and to the solution was added 0.6 ml of 2 N potassiumhydroxide aqueous solution. The mixture was refluxed for 10 hours, andafter the addition of 30 ml of saturated sodium chloride aqueoussolution, extracted twice with 20 ml of a mixed solvent ofchloroform/isopropanol (5:1). The extract was dried over magnesiumsulfate and concentrated under a reduced pressure, and a resultingresidue was applied to a silica gel column and eluted withchloroform/methanol (40:1 to 10:1) to obtain 74 mg of the title compoundin a colorless amorphous form.

IR (KBr) cm⁻¹ : 1630, 1510, 1440, 1320, 1230, 1150, 1128;

¹ H-NMR (CDCl₃, δ ppm): 1.65-1.83 (2H, m), 2.00-2.37 (6H, m), 2.57-2.80(4H, m), 3.02-3.42 (4H, m), 4.31 (1H, m), 6.30 (2H, d, J=8.3.Hz), 6.41(1H, d, J=9.3 Hz), 6.65 (2H, d, J=8.3 Hz), 7.15-7.37 (5H, m), 7.60 (1H,t, J=7.8 Hz), 8.16 (1H, d, J=8.3 Hz), 8.23-8.33 (2H, m), 8.58 (1H, br),9.33 (1H, br).

REFERENCE EXAMPLE 12 1-[N-(tert-Butoxycarbonyl)tyrosyl]-4-phenylpiperazine

19.7 g of N-(tert-butoxycarbonyl)tyrosine, 12.5 g of N-phenylpiperazineand 16.1 g of N-hydroxybenzotriazole were dissolved in 100 ml oftetrahydrofuran, and to the solution was added dropwise a solution of18.7 g of DCC in 50 ml of tetrahydrofuran for 20 minutes with icecooling, and the mixture was stirred for one hour. The reaction mixturewas filtered to remove insoluble matter, which was then washed with 300ml of ethyl acetate, and the filtrates were combined and concentratedunder a reduced pressure. The resulting residue was dissolved in 500 mlof ethyl acetate, and the solution was washed three times with saturatedsodium bicarbonate aqueous solution and once with saturated sodiumchloride aqueous solution, dried over magnesium sulfate, andconcentrated under a reduced pressure. The resulting residue was appliedto a silica gel column and eluted with ethyl acetate/hexane (1:2 to 1:1)to collect desired fractions, which were then combined and concentratedunder a reduced pressure. Resulting residue was dissolved in 100 ml ofethyl acetate, and the solution was allowed to stand overnight in arefrigerator and then filtered to remove insoluble matter. The filtratewas concentrated under a reduced pressure, subjected to azeatropicdistillation with benzene and dried under a reduced pressure to obtain40.0 g of the title compound in a colorless amorphous form.

IR (KBr) cm⁻¹ : 1700, 1620, 1220;

¹ H-NMR (DMSO.d₆, δ ppm): 1.33 (9H, s), 2.6-3.1 (6H, m), 3.4-3.7 (4H,m), 4.55 (1H, m), 6.64 (2H, d, J=8.2 Hz), 6.80 (1H, t, J=7.3 Hz), 6.90(2H, d, J=7.9 Hz), 7.02 (2H, d, J=8.2 Hz), 7.22 (2H, dd, J=7.3, 7.9 Hz),9.16 (1H, s).

REFERENCE EXAMPLE 131-[2-(tert-Butoxycarbonylamino)-3-(p-hydroxyphenyl)propyl]-4-phenylpiperazine

With ice cooling, to a solution of 8.0 g of lithium aluminum hydride in230 ml of tetrahydrofuran a solution of 28.0 g of aluminum chloride in230 ml of ether was added dropwise for 50 minutes, and after 15 minutesto the resulting solution was added dropwise a solution of 40.0 g of theamorphous compound obtained in Reference Example 12 in 230 ml oftetrahydrofuran, for 15 minutes. The reaction mixture was allowed tobecome a room temperature, and after the addition of 300 ml oftetrahydrofuran, stirred for 25 minutes. The mixture was filtered toremove insoluble matter which was then washed with tetrahydrofuran. Thecombined filtrate was concentrated under a reduced pressure, andresulting residue was applied to a silica gel column, and eluted withchloroform/methanol (20:1) to collect fractions, which were thenconcentrated under a reduced pressure. Then 100 ml of ethyl acetate wasadded to the residue to crystallize a product. The product was filteredto collect, and washed 5 times with a mother liquid and further 3 timeswith n-hexane and dried under a reduced pressure to obtain 24.1 g of thetitle compound as colorless crystals.

Melting point: 199°-202° C. (decomposed)

¹ H-NMR (DMSO-d₆, δ ppm): 1.33 (9H, s), 2.2-2.8 (8H, m), 3.09 (4H, brs),3.72 (1H, m), 6.5-7.0 (7H, m), 7.20 (2H, t, J=8.3 Hz), 9.10 (1H, s);

IR (KBr) cm⁻¹ : 1690, 1500, 1230.

REFERENCE EXAMPLE 141-[2-Amino-3-(p-hydroxyphenyl)propyl]-4-phenylpiperazine

To a suspension of 23.6 g of the crystals obtained in Reference Example13 in 100 ml of ethyl acetate, was added dropwise 215 ml of 4Nhydrochloric acid solution in ethyl acetate for 30 minutes, and afterstirring for 90 minutes, excess hydrochloric acid was removed from thereaction mixture under a reduced pressure. After extraction with 200 mlof water, the separated ethyl acetate layer was extracted with 50 ml of1N hydrochloric acid aqueous solution. The aqueous layers were combinedand neutralized to pH 7.4 with solid sodium bicarbonate, and resultingcrystals was collected, washed with water and benzene and dried byphosphorus pentaoxide in a desiccator under a reduced pressure to obtain16.9 g of the title compound as colorless crystals.

Melting point: >270° C.;

IR (KBr) cm⁻¹ : 1600, 1470, 1230;

¹ H-NMR (DMSO-d₆, δ ppm): 2.2-3.5 (13H, m), 6.7-6.8 (3H, m), 6.90 (2H,d, J=8.3 Hz), 7.07 (2H, d, J=8.3 Hz), 7.19 (2H, t, J=7.6 Hz), 8.00 (2H,brs), 9.41 (1H, brs).

EXAMPLE 34 N-{1-[p-(5-Isoquinolinesulfonyloxy)benzyl-2-(4-phenylpiperazinyl)ethyl}-5-isoquinolinesulfonamide

To a suspension of 22.96 g of the crystals obtained in Reference Example14 in 700 ml of tetrahydrofuran, was added 51.01 g of5-isoquinolinesulfonyl chloride.HCl with ice cooling for 5 minutes, andthen was added dropwise 103 ml of triethylamine for 30 minutes. Afterallowing to warm to a room temperature, the reaction mixture was pouredinto 460 ml of ice water, and the whole was extracted with 920 ml and230 ml of chloroform. The combined extract was washed with saturatedsodium chloride aqueous solution, dried over magnesium sulfate andconcentrated to dryness under a reduced pressure. The resultingamorphous residue was applied to a silica gel column and eluted withchloroform/methanol (100:1 to 50:1) to obtain 45.5 g of the titlecompound in a yellow amorphous form.

IR (KBr) cm⁻¹ : 1600, 1500, 1130;

¹ H-NMR (CDCl₃, δ ppm): 2.0-3.0 (12H, m), 3.30 (1H, m), 5.51 (1H, brs),6.7-7.8 (11H, m), 8.20 (1H, d, J=8.2 Hz), 8.28 (2H, d, J=7.7 Hz),8.4-8.5 (2H, m), 8.53 (1H, d, J=6.1 Hz), 8.67 (1H, d, J=6.1 Hz) 8.81(1H, d, J=6.1 Hz), 9.35 (1H, s), 9.42 (1H, s).

EXAMPLE 35 N-{1-[p-(5-Isoquinolinesulfonyloxy)benzyl]-2-(4-phenylpiperazinyl)ethyl}-N-methyl-5-isoquinolinesulfonamide

To a solution of 25.0 g of the amorphous compound obtained in Example 34in 200 ml of dimethylformamide was added in three portions 1.64 g of 60%sodium hydride, and after 5 minutes, also was added dropwise 3.14 ml ofmethyl iodide for two minutes, and the reaction mixture was stirred forone hour. The reaction mixture was poured to 400 ml of ice water, andthe whole was extracted with 200 ml, 200 ml and 100 ml of ethyl acetate.The combined extract was washed three times with saturated sodiumchloride aqueous solution, dried over magnesium sulfate and concentratedunder a reduced pressure, and the resulting residue was applied to asilica gel column and eluted with chloroform/methanol (100:1) to obtain20.0 g of the title compound in a yellow amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 2.30 (1H, dd, J=6.8, 12.2 Hz), 2.39-2.52 (5H,m), 2.68 (1H, dd, J=7.3, 14.2 Hz), 2.86 (3H, s), 2.89-3.01 (5H, m), 4.18(1H, m), 6.61 (2H, d, J=8.3 Hz), 6.83-6.92 (5H, m), 7.26 (2H, t, J=7.8Hz), 7.57 (1H, t, J=7.8 Hz), 7.60 (1H, t, J=7.8 Hz), 8.10 (1H, d, J=8.3Hz), 8.23-8.28 (3H, m), 8.33 (1H, dd, J=1.0, 7.3 Hz), 8.56 (1H, d, J=5.9Hz), 8.58 (1H, d, J=5.9 Hz), 8.83 (1H, d, J=5.9 Hz), 9.27 (1H, s), 9.41(1H, d, J=1.0 Hz).

IR (KBr) cm⁻¹ : 1620, 1500, 1370, 1325, 1130.

EXAMPLE 36N-[1-(p-Hydroxybenzyl)-2-(4-phenylpiperazinyl)ethyl]-N-methyl-5-isoquinolinesulfonamide

To 17.7 g of the amorphous compound obtained in Example 35 were added240 ml of methanol, 60 ml of tetrahydrofuran and 29 ml of 2N sodiumhydroxide aqueous solution, and the mixture was refluxed for 150minutes, and then poured to saturated sodium chloride aqueous solution.The mixture was extracted three times with 200 ml of chloroform, and theextract was washed with saturated sodium chloride aqueous solution,dried over magnesium sulfate, and concentrated under a reduced pressure.The resulting residue was applied to a silica gel column and eluted withchloroform/methanol (50:1), and 10.9 g of a yellow amorphous product wasobtained from the elute. To the product was added 54 ml of ethanol andthe mixture was stirred at a room temperature for one hour, and underice cooling for 30 minutes to form crystals, which was then collected,washed three times with a mother liquid and twice with benzene, anddried under a reduced pressure to obtain 8.2 g of the title compound aslight yellow crystals.

Melting point: 201° C.;

¹ H-NMR (CDCl₃, δ ppm): 2.49 (1H, dd, J=6.8, 9.8 Hz), 2.52-2.77 (7H, m),2.95 (1H, dd, J=4.4, 14.2 Hz), 3.02 (3H, s), 3.14 (4H, t, J=4.9 Hz),4.03 (1H, m), 6.26 (2H, d, J=8.3 Hz), 6.61 (2H, d, J=8.8 Hz), 6.86 (1H,t, J=6.8 Hz), 6.91 (2H, d, J=7.3 Hz), 7.27 (2H, t, J=7.8 Hz), 7.60 (1H,t, J=7.3 Hz), 8.11 (1H, d, J=5.9 Hz), 8.14 (1H, d, J=6.4 Hz), 8.33 (1H,dd, J=1.0, 7.3 Hz), 8.47 (1H, d, J=6.3 Hz), 9.27 (1H, s);

IR (KBr) cm⁻¹ : 1600, 1510, 1445, 1320, 1205, 1150, 1125.

EXAMPLE 37

The amorphous compound obtained in Example 34 was subjected to alkalinehydrolysis according to the procedure as described in Example 36, toobtainN-[1-(p-hydroxybenzyl)-2-(4-phenylpiperazinyl)ethyl]-5-isoquinolinesulfonamidein a colorless amorphous.

¹ H-NMR (CDCl₃, δ ppm): 2.25-2.55 (6H, m), 2.65 (1H, dd, J=13.7, 6.85Hz), 2.79 (1H, dd, J=13.7, 6.85 Hz), 2.82-3.0 (4H, m), 3.37 (1H,quintet, J=6.85 Hz), 6.42 (2H, d, J=8.57 Hz), 6.69 (2H, d, J=8.57 Hz),6.84 (2H, d, J=8.57 Hz), 6.85 (1H, t, J=8.57 Hz), 7.26 (2H, t, J=8.57Hz), 7.69 (1H, t, J=7.42 Hz), 8.22 (1H, d, J=7.99 Hz), 8.38 (1H, d,J=6.28 Hz), 8.43 (1H, dd, J=7.42, 1.0 Hz), 8.59 (1H, d, J=6.28 Hz), 9.34(1H, d, J=1.0 Hz).

EXAMPLE 38N-[1-(p-Methoxybenzyl)-2-(4-phenylpiperazinyl)ethyl]-N-methyl-5-isoquinolinesulfonamide

1.51 g of the crystals obtained in Example 36 was dissolved in 20 ml ofa mixed solvent of dimethylformamide/tetrahydrofuran (1:1), and to thesolution was added 140 mg of 60% sodium hydride with stirring under icecooling, and stirring was continued for about 30 minutes. After foamingwas finished, 490 mg of methyl iodide was added and the mixture wasfurther stirred overnight at a room temperature. After the addition ofice, the reaction mixture was three times extracted with 50 ml of ethylacetate, and the extract was washed with saturated sodium chlorideaqueous solution, dried over magnesium sulfate and concentrated under areduced pressure. The resulting residue was applied to a silicon gelcolumn and eluted with chloroform/methanol (100:1) to obtain 1.55 g ofthe title compound as a light brown oil.

¹ H-NMR (CDCl₃, δ ppm): 2.45 (1H, dd, J=7.1, 13.8 Hz), 2.6 (5H, m), 2.65(1H, m), 2.88 (1H, s), 2.95 (3H, s), 3.05 (4H, m), 3.74 (3H, s), 4.2(1H, m), 6.5 (2H, d, J=8.5 Hz), 6.9 (5H, m), 7.25 (2H, m), 7.55 (1H, t,J=7.5 Hz), 8.07 (1H, d, J=7.5 Hz), 8.22 (1H, d, J=6.4 Hz), 8.56 (1H, d,J=6.4 Hz), 9.22 (1H, s);

IR (KBr) cm⁻¹ : 1600, 1510, 1320, 1240, 1150, 1130.

EXAMPLE 39

The same procedures as described in Reference Examples 12 to 14 andExample 34 were repeated except that 1-(2-pyrimidyl)piperazine.dihydrochloride was used in place of N-phenylpiperazine, to obtainN-{1-[p-(5-isoquinolinesufonyloxy)benzyl]-2-[4-(2-pyrimidyl)piperazinyl]ethyl}-5-isoquinolinesulfonamidein a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.8-1.96 (2H, m), 1.96-2.24 (4H, m), 2.8 (1H,dd, J=13.7, 6.85 Hz), 2.92 (1H, dd, J=13.7, 4.57 Hz), 3.0-3.47 (5H, m),5.49 (1H, br), 6.47 (1H, t, J=4.57 Hz), 6.70 (2H, d, J=8.57 Hz), 6.94(2H, d, J=8.57 Hz), 7.64 (1H, t, J=7.42 Hz), 7.70 (1H, t, J=7.42 Hz),8.17-8.35 (5H, m), 8.37-8.48 (2H, m) 8.52 (1H, d, J=5.71 Hz), 8.68 (1H,d, J=6.28 Hz), 8.82 (1H, d, J=6.28 Hz) 9.37 (1H, s), 9.42 (1H, d, J=1.0Hz).

EXAMPLE 40

The amorphous compound of the Example 39 was treated as described inExample 37, to obtainN-{1-(p-hydroxybenzyl)-2-[4-(2-pyrimidyl)piperazinyl]ethyl}-5-isoquinolinesulfonamidein a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm) 2.05-2.55 (6H, m), 2.66 (1H, dd, J=13.13, 6.85Hz), 2.82 (1H, dd, J=13.13, 6.28 Hz), 3.2-3.7 (5H, m), 6.42 (2H, d,J=7.99 Hz), 6.46 (1H, t, J=4.57 Hz), 6.72 (2H, d, J=7.99 Hz), 7.68 (1H,t, J=7.42 Hz), 8.20 (1H, d, J=8.57 Hz), 8.27 (2H, d, J=4.57 Hz),8.35-8.50 (2H, m), 8.57 (1H, d, J=5.71 Hz), 9.31 (1H, s).

EXAMPLE 41

The amorphous compound of Example of 39 was treated as described inExample 35, to obtainN-{1-[p-(5-isoquinolinesulfonyloxy)benzyl]-2-[4-(2-pyrimidyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamidein a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm) 2.15-2.36 (5H, m), 2.44 (1H, dd, J=13.7, 6.85Hz), 2.71 (1H, dd, J=13.13, 6.85 Hz), 2.8-2.95 (1H, m), 2.87 (3H, s),3.56 (4H, m), 4.17 (1H, quintet, J=6.85 Hz), 6.48 (1H, t, J=4.85 Hz),6.63 (2H, d, J=9.14 Hz), 6.92 (2H, d, J=9.14 Hz), 7.58 (1H, t, J=6.85Hz), 7.61 (1H, t, J=6.85 Hz), 8.13 (1H, d, J=7.42 Hz), 8.18-8.38 (6H,m), 8.56 (1H, d, J=6.28 Hz), 8.58 (1H, d, J=6.28 Hz), 8.84 (1H, d,J=6.28 Hz), 9.28 (1H, s), 9.42 (1H, d, J=1.0 Hz)

EXAMPLE 42

The amorphous compound of Example 41 was treated as described in Example36, to obtainN-{1-(p-hydroxybenzyl)-2-[4-(2-pyrimidyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamidein a colorless amorphous form.

IR (KBr) cm⁻¹ : 1585, 1510, 1355, 1325, 1255, 1130;

¹ H-NMR (CDCl₃, δ ppm) 2.4-2.65 (6H, m), 2.70 (1H, dd, J=13.13, 6.28Hz), 2.97 (1H, dd, J=13.13, 5.71 Hz), 3.03 (3H, s), 3.77 (4H, t, J=4.57Hz), 4.04 (1H, m), 6.28 (2H, d, J=8.57 Hz), 6.49 (1H, t, J=5.14 Hz),6.62 (2H, d, J=8.57 Hz), 7.62 (1H, t, J=7.42 Hz), 8.11 (1H, d, J=6.28Hz), 8.15 (1H, d, J=7.42 Hz), 8.30 (2H, d, J=5.14 Hz), 8.32 (1H, dd,J=7.42, 1.0 Hz), 8.48 (1H, d, J=6.28 Hz), 9.28 (1H, s).

EXAMPLE 43

The same procedures as described in Reference Examples 12 to 14 andExamples 34 and 35 were repeated except thatN-(tert-butoxycarbonyl)phenylalanine was used in place ofN-(tert-butoxycarbonyl) tyrosine, to obtainN-[1-benzyl-2-(4-phenylpiperazinyl)ethyl]-N-methyl-5-isoquinolinesulfonamidein a light yellow amorphous form.

IR (KBr) cm⁻¹ : 1595, 1490, 1300, 1220, 1120;

¹ H-NMR (CDCl₃, δ ppm): 2.45 (1H, dd, J=6.6, 13 Hz), 2.7 (1H, dd, J=8,13 Hz), 2.55 (5H, m), 3.0 (5H, m), 4.3 (1H, m), 6.84, 6.9 (Total 3H, m),7.0 (5H, brs), 7.25 (2H, m), 7.5 (1H, t, J=7.5 Hz), 8.05 (1H, d, J=8Hz), 8.2 (1H, d, J=7.5 Hz), 8.3 (1H, d, J=8 Hz), 8.55 (1H, d, J=6.1 Hz),9.23 (1H, s).

EXAMPLE 44

The same procedures as described in Reference Examples 12 to 14 andExample 34 were repeated except that N-(2-pyridyl) piperazine was usedin place of N-phenylpiperazine, to obtainN-{1-[p-(5-isoquinolinesulfonyloxy)benzyl-2-[4-(2-pyridyl)piperazinyl]ethyl}-5-isoquinolinesulfonamidein a yellow amorphous form.

IR (KBr) cm⁻¹ : 1615, 1590, 1480, 1430, 1370, 1310, 1150, 1130;

¹ H-NMR (CDCl₃, δ ppm): 1.93-2.21 (6H, m), 2.77 (1H, dd, J=7.3, 14.2Hz), 2.83-3.00 (3H, m), 3.02-3.19 (2H, m), 3.29 (1H, m), 5.46 (1H, br),6.47 (1H, d, J=8.8 Hz), 6.62 (1H, dd, J=4.9, 7.3 Hz), 6.69 (2H, d, J=8.8Hz), 6.92 (2H, d, J=8.8 Hz), 7.44 (1H, ddd, J=1.0, 8.8, 7.3 Hz), 7.64(1H, t, J=7.8 Hz), 7.70 (1H, dd, J=7.3, 8.3 Hz), 8.13 (1H, dd, J=1.0,4.9 Hz), 8.22 (1H, d, J=8.3 Hz), 8.28 (2H, d, J=7.3 Hz), 8.43 (2H, m),8.53 (1H, d, J=5.9 Hz), 8.67 (1H, d, J=6.3 Hz), 8.81 (1H, d, J=5.9 Hz),9.35 (1H, d, J=1.0 Hz), 9.42 (1H, s).

EXAMPLE 45

The product of Example 44 was treated as described in Example 35 toobtainN-{1-[p-(5-isoquinolinesulfonyloxy)benzyl]-2-[4-(2-pyridyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamide.

IR (KBr) cm⁻¹ : 1590, 1480, 1430, 1370, 1310, 1130;

¹ H-NMR (CDCl₃, δ ppm): 2.23-2.50 (6H, m), 2.69 (1H, dd, J=7.3, 14.2Hz), 2.86 (3H, s), 2.88 (1H, dd, J=14.2, 10.2 Hz), 3.30 (4H, m), 4.18(1H, m), 6.55-6.65 (4H, m), 6.90 (2H, d, J=8.8 Hz), 7.47 (1H, ddd,J=1.0, 7.3, 8.8 Hz), 7.58 (1H, dd, J=7.3, 8.3 Hz), 7.60 (1H, t, J=7.8Hz), 8.11 (1H, d, J=8.3 Hz), 8.17 (1H, dd, J=1.0, 4.9 Hz), 8.22-8.27(3H, m), 8.33 (1H, dd, J=1.0, 7.3 Hz), 8.56 (1H, d, J=5.9 Hz), 8.58 (1H,d, J=5.9 Hz), 8.84 (1H, d, J=6.4 Hz), 9.28 (1H, s), 9.41 (1H, s).

EXAMPLE 46

The product of Example 45 was treated as described in Example 36 toobtainN-{1-(p-hydroxybenzyl)-2-[4-(2-pyridyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamide.

IR (KBr) cm⁻¹ : 1590, 1475, 1445, 1320, 1230, 1150, 1125;

¹ H-NMR (CDCl₃, δ ppm): 2.48 (1H, dd, J=3.4, 9.4 Hz), 2.50-2.75 (6H, m),2.95 (1H, dd, J=4.9, 14.7 Hz), 3.02 (3H, s), 3.49 (4H, t, J=4.9 Hz),4.06 (1H, m), 6.27 (2H, d, J=8.3 Hz), 6.62 (2H, d, J=8.3 Hz), 6.61-6.66(2H, m), 7.43 (1H, ddd, J=1.0, 7.3, 8.8 Hz), 7.61 (1H, dd, J=7.3, 8.3Hz), 8.10-8.16 (2H, m), 8.19 (1H, dd, J=1.0, 4.3 Hz), 8.32 (1H, dd,J=1.0, 7.3 Hz), 8.48 (1H, d, J=6.4 Hz), 9.28 (1H, s).

EXAMPLE 47

The same procedures as described in Reference Example 12 to 14 andExamples 34 to 36 were repeated except that N-(m-chlorophenyl)piperazinewas used in place of N-phenylpiperazine, to obtainN-{2-[4-(m-chlorophenyl)piperazinyl]-1-(p-hydroxybenzyl)ethyl}-N-methyl-5-isoquinolinesulfonamidein a light yellow amorphous form.

IR (KBr) cm⁻¹ : 1590, 1320, 1230, 1130;

¹ H-NMR (CDCl₃, δ ppm): 2.5 (1H, dd, J=12.0, 10 Hz), 2.5-2.8 (2H, m),2.6-2.7 (4H, m), 2.95 (1H, dd, J=4.5, 13.8 Hz), 3.0 (3H, s), 3.15 (4H,m), 4.0 (1H, m), 6.22 (2H, d, J=8.0 Hz), 6.55 (2H, d, J=8.0 Hz), 6.77(1H, dd, J=8.5, 2.2 Hz), 6.8 (1H, d, J=8.0 Hz), 6.85 (1H, d, J=2.2 Hz),7.16 (1H, t, J=8.0 Hz), 7.6 (1H, t, J=7.8 Hz), 8.1 (1H, d, J=6.1 Hz),8.15 (1H, d, J=8.1 Hz), 8.3 (1H, d, J=7.3 Hz), 8.45 (1H, d, J=6.4 Hz),9.28 (1H, s).

EXAMPLE 48

The same procedures as described in Reference Examples 12 to 14 andExample 34 were repeated except that N-(p-fluorophenyl)piperazine wasused in place of N-phenylpiperazine, to obtainN-{2-[4-(p-fluorophenyl)piperazinyl]-1-[p-(5-isoquinolinesulfonyloxy)benzyl]ethyl]}-5-isoquinolinesulfonamidein a colorless amorphous form.

IR (KBr) cm⁻¹ : 1610, 1500, 1370, 1320, 1210, 1130, 860, 820;

¹ H-NMR (CDCl₃, δ ppm): 2.0-2.3 (5H, m), 2.4-2.9 (6H, m), 3.3 (1H, m),6.6-6.75 (4H, m), 6.85-7.0 (4H, m), 7.65 (1H, t, J=8.1 Hz), 7.7 (1H, t,J=8.4 Hz), 8.2 (1H, d, J=8.3 Hz), 8.3 (1H, d, J=7.8 Hz), 8.4 (1H, d,J=6.3 Hz), 8.4 (1H, d, J=6.1 Hz), 8.5 (1H, d, J=6.1), 8.65 (1H, d, J=6.1Hz), 8.8 (1H, d, J=6.3 Hz), 9.3 (1H, s), 9.4 (1H, s).

EXAMPLE 49

The amorphous compound obtained in Example 48 was methylated accordingto the procedure described in Example 35 to obtainN-{2-[4-(p-fluorophenyl)piperazinyl]-1-[p-(5-isoquinolinesulfonyloxy)benzyl]ethyl]}-N-methyl-5-isoquinolinesulfonamidein a light yellow amorphous form.

IR (KBr) cm⁻¹ : 1620, 1510, 1370, 1330, 1210, 1140.

¹ H-NMR (CDCl₃, δ ppm): 2.3 (1H, dd, J=12.1, 6.5 Hz), 24.5 (4H, m),2.4-2.6 (1H, m), 2.67 (1H, dd, J=13.8, 7.8 Hz), 2.75-3.0 (5H, m), 4.17(1H, m), 6.63 (2H, d, J=8.6 Hz), 6.7-7.0 (6H, m), 7.57 (1H, t, J=8.0Hz), 7.60 (1H, t, J=7.6 Hz), 8.1 (1H, d, J=8.0 Hz), 8.2-8.35 (4H, m),8.55 (1H, d, J=5.4 Hz), 8.56 (1H, d, J=8.1 Hz), 8.83 (1H, d, J=6.3 Hz),9.27 (1H, d, J=0.7 Hz), 9.40 (1H, d, J=1.0 Hz).

EXAMPLE 50

According to the procedure described in Example 36, 160 mg of theamorphous compound obtained in Example 49 was dissolved in 2 ml ofmethanol, and to the solution was added 0.5 ml of 2N sodium hydroxide,and the reaction mixture was refluxed for two hours, cooled, andextracted three times with chloroform. The extract was purified on asilica gel column using chloroform/methanol (100:2), to obtain 103 mg ofN-{1-(p-hydroxybenzyl)-2-[4-(p-fluorophenyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamidein a light yellow amorphous form.

IR (KBr) cm⁻¹ : 1610, 1500, 1320, 1230, 1150, 1130, 820;

¹ H-NMR (CDCl₃, δ ppm): 2.4-2.6 (2H, m), 2.6-2.8 (1H, m), 2.8-3.0 (1H,m), 2.75 (4H, m), 3.05 (1H, m), 3.1 (1H, m), 6.3 (2H, d, J=8.3 Hz), 6.67(2H, d, J=8.3 Hz), 6.87 (2H, dd, J=8.3, 10.1 Hz), 6.95 (2H, t, J=8.3Hz), 7.6 (1H, dd, J=7.6, 8.0 Hz), 8.12 (1H, d, J=9.0 Hz), 8.13 (1H, d,J=6.1 Hz), 8.3 (1H, d, J=7.3 Hz), 8.5 (1H, d, J=6.1 Hz), 9.25 (1H, s).

EXAMPLE 51

The same procedures as described in Reference Examples 12 to 14 andExamples 34 to 36 were repeated except that N-(m-methylphenyl)piperazinewas used in place of N-phenylpiperazine, to obtainN-{1-(p-hydroxybenzyl)-2-[4-(m-methylphenyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamidein a light yellow amorphous form.

IR (KBr) cm⁻¹ : 1600, 1440, 1320, 1210, 1190, 1150, 1120;

¹ H-NMR (CDCl₃, δ ppm): 2.30 (3H, s), 2.55 (4H, m), 2.96 (1H, dd,J=11.6, 7.1 Hz), 2.5-2.9 (3H, m), 2.9 (3H, s), 3.1 (4H, m), 4.3 (1H, m),6.8 (2H, d, J=8.3 Hz), 7.0 (2H, d, J=8.3 Hz), 7.0-7.15 (3H, m), 7.3 (1H,m), 7.55 (1H, t, J=7.8 Hz), 8.1 (1H, d, J=7.8 Hz), 8.2-8.3 (2H,complex), 8.58 (1H, d, J=6.1 Hz), 9.25 (1H, s).

EXAMPLE 52

The same procedures as described in reference Examples 12 to 14 andExample 34 were sequentially repeated except thatN-(p-methoxyphenyl)piperazine was used in place of N-phenylpiperazine,to obtainN-{1-[p-(5-isoquinolinesulfonyloxy)benzyl-2-[4-(p-methoxyphenyl)piperazinyl]ethyl}-5-isoquinolinesulfonamidein yellow amorphous form.

IR (KBr) cm⁻¹ : 1615, 1500, 1360, 1130;

¹ H-NMR (CDCl₃, δ ppm): 1.96-2.22 (6H, m), 2.39-2.52 (2H, m), 2.52-2.67(2H, m), 2.77 (1H, dd, J=7.3, 14.2 Hz), 2.90 (1H, dd, J=4.4, 14.2 Hz),3.27 (1H, m), 3.76 (3H, s), 5.50 (1H, br), 6.70 (4H, d, J=8.8 Hz), 6.82(2H, d, J=8.8 Hz), 6.94 (2H, d, J=8.8 Hz), 7.65 (1H, t, J=7.8 Hz), 7.70(1H, t, J=7.3 Hz), 8.21 (1H, d, J=8.3 Hz), 8.29 (2H, d, J=7.8 Hz),8.40-8.43 (2H, m), 8.53 (1H, d, J=5.9 Hz), 8.68 (1H, d, J=6.4 Hz), 8.81(1H, d, J=5.9 Hz), 9.36 (1H, s), 9.42 (1H, s).

EXAMPLE 53

The amorphous compound of Example 52 was treated with methyl iodideaccording to the procedure described in Example 35 to obtainN-{1-[p-(5-isoquinolinesulfonyloxy)benzyl]-2-[4-(p-methoxyphenyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamidein a yellow amorphous form.

IR (KBr) cm⁻¹ : 1665, 1615, 1505, 1365, 1320, 1130;

¹ H-NMR (CDCl₃, δ ppm): 2.30 (1H, dd, J=6.8, 12.2 Hz), 2.37-2.51 (5H,m), 2.68 (1H, dd, J=7.3, 14.2 Hz), 2.85 (3H, s), 2.78-2.97 (5H, m), 3.77(3H, s), 4.16 (1H, m), 6.62 (2H, d, J=8.3 Hz), 6.82 (4H, s), 6.90 (2H,d, J=8.3 Hz), 7.57 (1H, t, J=7.8 Hz), 7.60 (1H, t, J=7.8 Hz), 8.11 (1H,d, J=8.3 Hz), 8.23-8.28 (3H, m), 8.33 (1H, dd, J=1.0, 7.3 Hz), 8.56 (1H,d, J=6.4 Hz), 8.58 (1H, d, J=6.4 Hz), 8.83 (1H, d, J=5.9 Hz), 9.27 (1H,d, J=1.0 Hz), 9.41 (1H, d, J=1.0 Hz).

EXAMPLE 54

The amorphous compound obtained in Example 53 was subjected to alkalinehydrolysis according to the procedure described in Example 36 to obtainN-{1-(p-hydroxybenzyl)-2-[4-(p-methoxyphenyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamideas yellow crystals,

Melting point: 157°-160° C. (decomposed);

IR (KBr) cm⁻¹ : 1615, 1510, 1445, 1320, 1305, 1240 1125;

¹ H-NMR (CDCl₃, δ ppm): 2.46-2.74 (7H, m), 2.88-3.02 (5H, m), 3.00 (3H,s), 3.77 (3H, s), 4.06 (1H, m), 6.30 (2H, d, J=8.3 Hz), 6.65 (2H, d,J=8.3 Hz), 6.83 (2H, d, J=9.3 Hz), 6.88 (2H, d, J=9.3 Hz), 7.57 (1H, dd,J=7.3, 8.3 Hz), 8.12 (1H, d, J=8.3 Hz), 8.13 (1H, d, J=6.4 Hz), 8.32(1H, dd, J=1.0, 7.3 Hz), 8.50 (1H, d, J=6.4 Hz), 9.26 (1H, s).

EXAMPLE 55

The amorphous compound obtained in Example 52 was subjected to alkalinehydrolysis according to the procedure described in Example 37, to obtainN-{1-(p-hydroxybenzyl)-2-[4-(p-methoxyphenyl)piperazinyl]ethyl}-5-isoquinolinesulfonamide as yellow crystals.

Melting point: 200°-208° C. (decomposed);

IR (KBr) cm⁻¹ : 1615, 1590, 1510, 1450, 1340, 1230, 1150, 1130, 1025;

¹ H-NMR (CDCl₃, δ ppm): 2.20-2.44 (6H, m), 2.58-2.82 (6H, m), 3.33 (1H,m), 3.77 (3H, s), 5.55 (1H, br), 6.47 (2H, d, J=8.3 Hz), 6.76 (2H, d,J=8.3 Hz), 6.78 (2H, d, J=6.8 Hz), 6.83 (2H, d, J=6.8 Hz), 7.70 (1H, t,J=7.8 Hz), 8.21 (1H, d, J=8.3 Hz), 8.40 (1H, d, J=6.4 Hz), 8.44 (1H, dd,J=1.0, 7.3 Hz), 8.64 (1H, d, J=6.4 Hz), 9.34 (1H, s).

EXAMPLE 56

The same procedures as described in Reference Examples 12 to 14 andExamples 34 and 35 were sequentially repeated except thatN-(2-methoxyphenyl)piperazine was used in place of N-phenylpiperazine toobtainN-{1-[p-(5-isoquinolinesulfonyloxy)benzyl]-2-[4-(2methoxyphenyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamide,and 800 mg of the compound was subjected to alkaline hydrolysisaccording to the procedure described in Example 36 to obtain 504 mg ofN-{1-(p-hydroxybenzyl)-2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamidein a light yellow amorphous form.

IR (KBr) cm⁻¹ : 1610, 1590, 1500, 1320, 1230, 1130;

¹ H-NMR (CDCl₃, δ ppm): 2.5 (1H, dd, J=13.8, 10.0 Hz), 2.55-2.8 (2H, m),2.9-3.0 (1H, m), 2.7 (4H, m), 3.0 (4H, m), 3.05 (3H, s), 3.86 (3H, s),4.0 (1H, m), 6.23 (2H, d, J=8.3 Hz), 6.57 (2H, d, J=8.3 Hz), 6.8-7.1(4H, m), 7.6 (1H, t, J=8.0 Hz), 8.14 (1H, d, J=6.1 Hz), 8.16 (1H, d,J=7.9 Hz), 8.35 (1H, dd, J=7.4, 1.0 Hz), 9.30 (1H, s).

EXAMPLE 57

1-[2-Amino-3-(p-hydroxyphenyl)propyl]-4-phenylpiperazine in crystalsobtained in Reference Example 14 was reacted with 1-naphtharenesulfonylchloride according to the procedure of Example 34, and the product thusobtained was treated with methyl iodide according to the proceduredescribed in Example 35, to obtainN-methyl-N-{1-[p-(α-naphtharenesulfonyloxy)-benzyl]-2-(4-phenylpiperazinyl)ethyl}-α-naphtharenesulfonamidein colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 2.26 (1H, dd, J=12.56, 6.85 Hz), 2.42 (4H,m),2.48 (1H, dd, J=12.56, 6.85 Hz), 2.68 (1H, dd, J=14.85, 6.85 Hz), 2.84(1H, dd, J=14.85, 6.85 Hz), 2.85 (3H, s), 2.92 (4H,m), 4.12 (1H,quintet, J=6.85 Hz), 6.56 (2H, d, J=8.0 Hz), 6.78-6.92 (5H, m), 7.26(2H, t, J=8.0 Hz), 7.42 (2H, t, J=8.0 Hz), 7.46-7.58 (2H, m), 7.68 (1H,dt, J=8 0, 1.0 Hz), 7.77-7.90 (2H, m), 7.90-8.07 (3H, m), 8.12 (1H, d,J=8.57 Hz), 8.17 (1H, dd, J=8.57, 1.0 Hz), 8.45 (1H, m), 8.84 (1H, d,J=9.14 Hz).

EXAMPLE 58

The amorphous compound obtained in Example 57 was subjected to alkalinehydrolysis according to the procedure described in Example 36, to obtainN-[1-(p-hydroxybenzyl)-2-.4(-phenylpiperazinyl)ethyl]-N-methyl-α-naphtharenesulfonamidein a colorless amorphous form.

IR (KBr) cm⁻¹ : 1595, 1315, 1310, 1225, 1150, 1120;

¹ H-NMR (CDCl₃, δ ppm): 2.37 (1H, dd, J=13.70, 6.85 Hz), 2.47 (4H, m),2.55 (1H, dd, J=13.70, 6.85 Hz), 2.72 (1H, dd, J=14.28, 6.85 Hz), 2.85(1H, dd, J=14.28, 6.85 Hz), 2.89 (3H, s), 2.97 (4H, m), 4.27 (1H,quinted, J=6.85 Hz), 5.10 (1H, br), 6.57 (2H, d, J=7.99 Hz), 6.78-6.89(3H, m), 6.91 (2H, d, J=7.99 Hz), 7.25 (2H, t, J=7.99 Hz), 7.43 (1H, t,J=7.42 Hz), 7.50-7.63 (2H, m), 7.86 (1H, dd, J=7.99, 1.0 Hz), 7.98 (1H,d, J=7.42 Hz), 8.22 (1H, dd, J= 7.42, 1.0 Hz), 8.56 (1H, dd, J=7.99, 1.0Hz).

REFERENCE EXAMPLE 151-{[2-Amino-3-(p-hydroxy)phenyl]propyl)-4-benzyloxycarbonylpiperazine

1.41 g of1-(N-tert-butoxycarbonyltyrosyl)-4-(benzyloxycarbonyl)piperazineprepared according to the procedure described in Reference Example 11was dissolved in 5.6 ml of absolute ethyl acetate, and to the solutionwas added dropwise 11.25 ml of 4N hydrogen chloride in ethyl acetatewith stirring under ice cooling for two minutes, and the reactionmixture was stirred for 2 hours at a room temperature. After thereaction was completed, the solvent was evaporated off under a reducedpressure, and to the residue was added 20 ml of 5% sodium bicarbonateaqueous solution. The mixture was extracted with 30 ml and then 20 ml ofa mixed solvent of chloroform/methanol (9:1), and the extract was washedwith saturated sodium chloride aqueous solution, dried over magnesiumsulfate and filtrated.

The filtrate was evaporated under a reduced pressure to obtain acolorless foam. The foam was applied to a silica gel column and elutedwith chloroform/methanol (6:1), to obtain about 700 mg of the titlecompound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 2.2-2.8 (8H, m), 3.19 (1H, m), 3.50 (7H, brs),5.13 (2H, s), 6.71 (2H, d, J=8.5 Hz), 7.02 (2H, d, J=8.5 Hz), 7.35 (5H,s).

EXAMPLE 59N-{2-(4-Benzyloxycarbonylpiperazinyl)-1-[p-(5-isoquinolinesulfonyloxy)benzyl]-ethyl}-5-isoquinolinesulfonamide

680 mg of the amorphous compound obtained in Reference Example 15 wasdissolved in 18 ml of absolute tetrahydrofuran, and to the solution wasadded 1.27 g of 5-isoquinolinesulfonyl chloride.HCl, and then was addeddropwise 3.20 ml of triethylamine with stirring under ice cooling forone minute, and the mixture was stirred at a room temperature for 150minutes. The reaction mixture was diluted with 50 ml of chloroform,washed with water, and the washings was extracted with 20 ml ofchloroform. The combined organic extract was washed with saturatedsodium chloride aqueous solution, dried over magnesium sulfate andfiltered, and the filtrate was evaporated under a reduced pressure. Theresulting residue was applied to a silica gel column, and eluted withchloroform/methanol (100:1) to obtain 987 mg of the title compound in alight yellow amorphous form.

IR (KBr) cm⁻¹ : 1700, 1620, 1500, 1370, 1230, 1130;

¹ H-NMR (CDCl₃, δ ppm): 1.8-2.2 (6H, m), 2.7-3.4 (7H, m), 5.05 (2H, s),5.36 (1H, brs), 6,67 (2H, d, J=8.4 Hz), 6.89 (2H, d, J=8.4 Hz), 7.2-7.4(5H, m), 7.62 (1H, d, J=7.7 Hz), 7.69 (1H, d, J=7.7 Hz), 8.2-8.5 (5H,brs), 8.52 (1H, d, J=6.2 Hz), 8.68 (1H, d, J=6.2 Hz), 8.81 (1H, d, J=5.9Hz), 9.34 (1H, s), 9.41 (1H, s).

EXAMPLE 60N-{2-(4-Benzyloxycarbonylpiperazinyl)-1-[p-(5-isoquinolinesulfonyloxy)benzyl]-ethyl}-N-methyl-5-isoquinolinesulfonamide

852 mg of the amorphous compound obtained in Example 59 was dissolved in8.5 ml of absolute dimethylformamide, and to the solution was added 59mg of 60% sodium hydride with stirring under ice cooling, and furtherwas added 113 μl of methyl iodide, and the reaction mixture was stirredfor 2 hours with ice cooling. After the addition of 30 ml of ice water,the reaction mixture was extracted with 30 ml, 20 ml and 20 ml of ethylacetate, the combined extract was washed with saturated sodium chlorideaqueous solution, dried over magnesium sulfate, filtered andconcentrated under a reduced pressure. The resulting residue was appliedto a silica gel column and eluted with chloroform/methanol (100:1) toobtain 679 mg of the title compound in a light yellow amorphous form.

IR (KBr) cm⁻¹ : 1700, 1620, 1500, 1370, 1240, 1130;

¹ H-NMR (CDCl₃, δ ppm): 2.23 (5H, brs), 2.3-2.9 (3H, m), 2.83 (3H, s),3.25 (4H, brs), 4.09 (1H, m), 5.11 (2H, s), 6.60 (2H, d, J=8.7 Hz), 6.86(2H, d, J=8.7 Hz), 7.34 (5H, brs), 7.5-7.7 (2H, m), 8.12 (1H, d, J=8.2Hz), 8.1-8.3 (4H, m), 8.56 (2H, m), 8.84 (1H, d, J=6.1 Hz), 9.29 (1H,s), 9.41 (1H, s).

EXAMPLE 61N-{2-(4-Benzenesulfonyl)piperazinyl-1-[p-(5-isoquinolinesulfonyloxy)benzyl]-ethyl}-N-methyl-5-isoquinolinesulfonamide

To 480 mg of the amorphous compound obtained in Example 60 was added 3ml of a solution of 30% hydrogen bromide in acetic acid, and the mixturewas stirred at a room temperature for 80 minutes. Then 50 ml of etherwas added to the mixture, which was then stirred. The resultingprecipitate was collected and washed with ether and dried under areduced pressure to obtain 567 mg ofN-{1-[p-(5-isoquinolinesulfonyloxy)benzyl]-2-piperazinyl-ethyl}-N-methyl-5-isoquinolinesulfonamide.HBras colorless crystals.

¹ H-NMR (DMSO-d₆ +D₂ O, δ ppm): 3.06 (3H, s), 3.46 (12H, brs), 4.24 (1H,brs), 6.08 (2H, d, J=8.5 Hz), 6.74 (2H, d, J=8.5 Hz), 7.93 (2H, m), 8.25(1H, d, J=6.7 Hz), 8.35 (1H, d, J=7.3 Hz), 8.5-8.8 (5H, m), 9.05 (1H, d,J=6.4 Hz), 9.86 (2H, brs).

550 mg of the crystals thus obtained was suspended in 10 ml of absolutetetrahydrofuran, and after stirring with ice cooling, to the suspensionwere added 84 μl of benzenesulfonyl chloride and 767 μl oftriethylamine, and the reaction mixture was stirred at a roomtemperature for 140 minutes. Then 30 ml of chloroform and 20 ml of waterwere added to the reaction mixture, and after separation of the layers,the aqueous layer was extracted with 20 ml of chloroform. The chloroformlayers were combined, washed with saturated sodium chloride aqueoussolution, dried over magnesium sulfate, and filtered. The filtrate wasevaporated under a reduced pressure, and the resulting residue wasapplied to a silica gel column and eluted with chloroform/methanol(100:1) to obtain 331 mg of the title compound in a light yellowamorphous form.

IR (KBr) cm⁻¹ : 1620, 1500, 1440, 1330, 1170;

¹ H-NMR (CDCl₃, δ ppm): 2.1-2.5 (6H, m), 2.5- 2.8 (6H, m), 2.78 (3H, s),4.05 (1H, m), 6.60 (2H, d, J=8.7 Hz), 6.83 (2H, d, J=8.7 Hz), 7.37 (1H,t, J=7.8 Hz), 7.5-7.8 (6H, m), 7.98 (1H, d, J=7.9 Hz), 8.1-8.3 (4H, m),8.49 (1H, d, J=6.1 Hz), 8.55 (1H, d, J=6.1 Hz), 8.84 (1H, d, J=6.1 Hz),9.17 (1H, s), 9.42 (1H, s).

EXAMPLE62N-{2-[(4-Benzenesulfonyl)piperazinyl)-1-(p-hydroxybenzyl)-ethyl}-N-methyl-5-isoquinolinesulfonamide

221 mg of the amorphous compound obtained in Example 61 was dissolved ina mixed solution of 2.69 ml of methanol and 0.66 ml of tetrahydrofuran,and to the solution was added 0.33 ml of 2N sodium hydroxide aqueoussolution. The reaction mixture was refluxed for 3.5 hours, and to themixture were added 30 ml of chloroform and 20 ml of 10% ammoniumchloride aqueous solution, and the resulting layers were separated. Theaqueous layer was extracted with 20 ml of chloroform, and the chloroformlayers were combined, washed with saturated sodium chloride aqueoussolution, dried over magnesium sulfate and filtered. The filtrate wasevaporated under a reduced pressure, and the resulting residue wasapplied to a silica gel column and eluted with chloroform/methanol(100:1) to obtain 146 mg of the title compound in a colorless amorphousform.

IR (KBr) cm⁻¹ : 1620, 1510, 1440, 1320, 1160;

¹ H-NMR (CDCl₃, δ ppm): 2.3-2.5 (2H, m), 2.60 (4H, brs), 2.6-2.8 (2H,m), 2.95 (3H, s), 3.01 (4H, brs), 3.92 (1H, brs), 6.21 (2H, d, J=8.2Hz), 6.51 (2H, d, J=8.2 Hz), 7.4-7.8 (6H, m), 8.03 (1H, d, J=6.1 Hz),8.09 (1H, d, J=8.2 Hz), 8.24 (1H, dd, J=1.2, 7.3 Hz), 8.40 (1H, d, J=5.8Hz), 8.68 (1H, brs), 9.23 (1H, brs).

REFERENCE EXAMPLE 16 O-Benzyl-N-benzyloxycarbonyltyrosinol

27.25 g of O-benzyl-N-benzyloxycarbonyltyrosine methyl ester wasdissolved in a mixed solvent of 185 ml of ethanol and 122 ml oftetrahydrofuran, and to the solution were added 5.8 g of lithiumchloride and 5.2 g of sodium borohydride under ice cooling. The reactionmixture was stirred at a room temperature for 18 hours, and after theaddition of 500 ml of saturated sodium chloride aqueous solution,extracted twice with 300 ml of chloroform. The extract was dried overmagnesium sulfate and concentrated under a reduced pressure to obtain25.4 g of the title compound as colorless crystals.

¹ H-NMR (CDCl₃, δ ppm): 2.79 (2H, d, J=7.4 Hz), 3.51-3.79 (2H, m), 3.89(1H, m), 4.93 (1H, br), 5.04 (2H, s), 5.08 (2H, s), 6.90 (2H, d, J=8.6Hz), 7.11 (2H, d, J=8.6 Hz), 7.26-7.46 (5H, m).

REFERENCE EXAMPLE 171-[2-Benzyloxycarbonylamino-3-(p-benzyloxyphenyl)propyl]-4-(tert-butoxycarbonyl)piperazine

5.6 g of the crystals obtained in Reference Example 16 was dissolved in70 ml of carbon tetrachloride, and after the addition of 4.5 g oftriphenylphosphine, the mixture was refluxed for 20 hours. The reactionmixture was filtered to remove insoluble matter, and the filtrate wasconcentrated under a reduced pressure, and the resulting residue wasapplied to a silica gel column and eluted with hexane/ethyl acetate(6:1) to obtain 4.96 g of2-benzyloxycarbonylamino-3-(p-benzyloxyphenyl)propyl chloride ascolorless crystals.

¹ H-NMR (CDCl₃, δ ppm): 2.76-2.90 (2H, m), 3.56-3.80 (2H, m), 4.39 (1H,m), 5.03 (2H, s), 5.05, 5.13 (Total 2H, each s), 6.85, 6.89 (Total 2H,each d, each J=8.3 Hz), 7.00, 7.09 (Total 2H, each d, each J=8.3 Hz),7.23-7.45 (5H, m).

4.1 g of the above-crystals and 2.23 g ofN-(tert-butoxycarbonyl)piperazine were dissolved in 40 ml ofdimethylformamide, to the solution were added 1.8 g of methyl iodide and1.66 g of potassium carbonate, and the mixture was stirred at 120° C.for 3 hours. After the addition of 100 ml of saturated sodium chlorideaqueous solution, the reaction mixture was extracted twice with 60 ml ofchloroform, and the extract was dried over magnesium sulfate andconcentrated under a reduced pressure. The resulting residue was appliedto a silica gel column and eluted with hexane/ethyl acetate (2:1) toobtain 2.69 g of the title compound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.45 (9H, s), 2.22-2.49 (6H, m), 2.82 (2H, m),3.36 (4H, m), 3.94 (1H, m), 4.83 (1H, br), 8.03 (2H, s), 5.09 (2H, s),6.88 (2H, d, J=8.3 Hz), 7.06 (2H, d, J=8.3 Hz), 7.30-7.45 (5H, m).

EXAMPLE 63N-{2-4-(tert-Butoxycarbonyl)piperazinyl]-1-[p-(5-isoquinolinesulfonyloxy)benzyl]-ethyl)-5-isoquinolinesulfonamide

1.6 g of the amorphous compound obtained in Reference Example 17 wasdissolved in 25 ml of methanol, and to the solution was added 1.0 g of5% palladium on carbon. The mixture was stirred in a hydrogen atmospherefor 20 hours, and filtered to remove insoluble matter. The filtrate wasconcentrated under a reduced pressure, resulting residue was dissolvedin 30 ml of tetrahydrofuran, and to the solution were added 2.8 g of5-isoquinolinesulfonyl chloride.HCl and 4 ml of triethylamine under icecooling. After stirring at a room temperature for 3 hours, to thereaction mixture was added 100 ml of water, and the mixture wasextracted twice with 70 ml of chloroform, and the extract was dried overmagnesium sulfate and concentrated under a reduced pressure. Theresulting residue was applied to a silica gel column and eluted withchloroform/methanol (100:1 to 50:1) to obtain 1.27 g of the titlecompound in a yellow amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.40 (9H, s), 1.75-2.18 (6H, m), 2.15-3.07 (6H,m), 3.27 (1H, m), 5.35 (1H, br), 6.67 (2H, d, J=8.3 Hz), 6.90 (2H, d,J=8.3 Hz), 7.65 (1H, t, J=7.8 Hz), 7.69 (1H, t, J=7.8 Hz), 8.21 (1H, d,J=8.3 Hz), 8.27-8.32 (2H, m), 8.37-8.41 (2H, m), 8.53 (1H, d, J=6.4 Hz),8.69 (1H, d, J=6.9 Hz), 8.82 (1H, d, J=6.4 Hz), 9.36 (1H, s), 9.43 (1H,s).

EXAMPLE 64

940 mg of the amorphous compound obtained in Example 63 was dissolved ina mixed solvent of 7.5 ml of tetrahydrofuran and 7.5 ml ofdimethylformamide, and to the solution were sequential added 67 mg of60% sodium hydride and 0.11 ml of methyl iodide under ice cooling, andthe mixture was stirred at a room temperature for one hour. After theaddition of 30 ml of saturated sodium chloride aqueous solution, thereaction mixture was extracted with 40 ml of ethyl acetate, and theextract was washed with saturated sodium chloride aqueous solution,dried over magnesium sulfate and concentrated under a reduced pressure.Resulting residue was applied to a silica gel column and eluted withchloroform/methanol (60:1) to obtain 723 mg ofN-{2-[4-(tert-butoxycarbonyl)piperazinyl]-[p-(5-isoquinolinesulfonyloxy)benzyl]-ethyl}-N-methyl-5-isoquinolinesulfonamidein a yellow amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.44 (9H, s), 2.21 (5H, m), 2.40 (1H, dd, J=6.9,12.6 Hz), 2.15 (1H, dd, J=7.4, 14.3 Hz), 2.83 (1H, dd, J=6.9, 14.3 Hz),2.84 (3H, s), 3.17 (9H, m), 4.12 (1H, m), 6.60 (2H, d, J=8.8 Hz), 6.86(2H, d, J=8.8 Hz), 7.58 (1H, t, J=7.8 Hz), 7.63 (1H, t, J=7.8 Hz), 8.13(1H, d, J=8.3 Hz), 8.21-8.30 (4H, m), 8.56 (1H, d, J=6.9 Hz), 8.57 (1H,d, J=5.9 Hz), 8.84 (1H, d, J=5.9 Hz), 9.29 (1H, s), 9.42 (1 H, s).

EXAMPLE 65

To 720 mg of the amorphous compound obtained in Example 64 was added 10ml of 4N hydrochloric acid in ethyl acetate, and the mixture was stirredat a room temperature for one hour and concentrated under a reducedpressure. To the mixture was added 30 ml of saturated sodium bicarbonateaqueous solution, and the reaction mixture was extracted twice with 20ml of a mixed solvent of chloroform/isopropanol (5:1). The extract wasdried over magnesium sulfate and concentrated to dryness under a reducedpressure to obtain 620 mg ofN-{1-[p-(5-isoquinolinesulfonyloxy)benzyl]-ethyl-2-piperazinyl}-N-methyl-5-isoquinolinesulfonamidein a yellow amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 2.18-2.28 (5H, m), 2.37 (1H, dd, J=7.3, 12.7Hz), 2.63 (4H, m), 2.66 (1H, dd, J=7.3, 14.8 Hz), 2.83 (3H, s), 2.86(1H, dd, J=5.4, 14.8 Hz), 4.13 (1H, m), 6.61 (2H, d, J=8.8 Hz), 6.89(2H, d, J=8.8 Hz), 7.59 (1H, t, J=7.8 Hz), 7.63 (1H, t, J 7.8 Hz), 8.12(1H, d, J=8.3 Hz), 8.23-8.35 (4H, m), 8.56 (1H, d, J=5.9 Hz), 8.58 (1H,d, J=6.4 Hz), 8.83 (1H, d, J=6.9 Hz), 9.29 (1H, s), 9.42 (1H, s).

EXAMPLE 66

620 mg of the amorphous compound obtained in Example 65 was dissolved in10 ml of methylene chloride, to the solution were added 0.29 ml ofbenzyl chloroformate and 0.4 ml of triethylamine with ice cooling. Thereaction mixture was stirred for two hours with ice cooling, and afterthe addition of 40 ml of saturated sodium chloride aqueous solution,extracted twice with 20 ml of chloroform. The extract was dried overmagnesium sulfate and concentrated under a reduced pressure, andresulting residue was applied to a silica gel column and eluted withchloroform/methanol (60:1) to obtain 660 mg of light yellow amorphousproduct showing the same ¹ H-NMR spectrum as that of the compound ofExample 60.

EXAMPLE 67

650 mg of the amorphous compound obtained in Example 66 was dissolved in6 ml of methanol, and to the solution was added 2 ml of 1N sodiumhydroxide aqueous solution. The mixture was refluxed for 2 hours, andafter the addition of 30 ml of saturated sodium chloride aqueoussolution, extracted twice with 200 ml of a mixed solvent ofchloroform/isopropanol (5:1). The extract was dried over magnesiumsulfate and concentrated under a reduced pressure, and resulting residuewas applied to a silica gel column and eluted with chloroform/methanol(80:1 to 50:1) to obtain 386 mg ofN-[2-(4-benzyloxycarbonyl-piperazinyl)-1-(p-hydroxybenzyl)ethyl]-N-methyl-5-isoquinolinesulfonamidein a yellow amorphous form.

IR (KBr) cm⁻¹ : 1693, 1510, 1425, 1320, 1235, 1120;

¹ H-NMR (CDCl₃, δ ppm): 2.39-2.55 (6H, m), 2.64 (1H, dd, J=6.4, 12.7Hz), 2.87 (1H, dd, J=4.4, 14.6 Hz), 2.97 (3H, s), 3.44 (4H, m), 4.03(1H, m], 5.13 (2H, s), 6.28 (2H, d, J=8.3 Hz), 6.62 (2H, d, J=8.3 Hz),7.36 (5H, s), 7.39 (1H, dd, J=7.3, 7.8 Hz), 8.09 (1H, d, J=5.9 Hz), 8.13(1H, d, J=7.8 Hz), 8.26 (1H, d, J=7.3 Hz), 8.48 (1H, d, J=5.9 Hz], 9.27(1H, s).

EXAMPLE 68

In the amorphous compound obtained in Example 63, protecting group ofthe piperazine moiety was removed according to the procedure describedin Example 65, and the deprotected intermediate was treated according tothe procedures described in Examples 66 and 67 to obtainN-[2-(4-benzyloxycarbonylpiperazinyl)-1-(p-hydroxybenzyl)ethyl]-5-isoquinolinesulfonamide.

IR (KBr) cm⁻¹ : 1670, 1510, 1425, 1320, 1230, 1150, 1125, 993;

1H-NMR (CDCl₃, δ ppm): 2.07-2.23 (4H, m), 2.30 (1H, dd, J=6.3, 13.2 Hz),2.39 (1H, dd, J=7.8, 13.2 Hz), 2.62 (1H, dd, J=6.8, 14.2 Hz), 2.76 (1H,dd, J=6.4, 14.2 Hz), 3.00-3.38 (5H, m), 5.09 (2H, s), 6.41 (2H, d, J=8.3Hz), 6.69 (2H, d, J=8.8 Hz), 7.33 (5H, s), 7.68 (1H, dd, J=7.3, 8.3 Hz)8.21 (1H, d, J=8.3 Hz), 8.35 (1H, d, J=5.9 Hz), 8.40 (1H, dd, J=1.0, 7.3Hz), 8.61 (1H, d, J=5.9 Hz), 9.34 (1H, s).

EXAMPLE 69

The same procedure as described in Example 68 was repeated except thatphenylpropionyl chloride was used in place of benzyl chloroformate, toobtainN-{1-(p-hydroxybenzyl)-2-[4-(3-phenylpropyl)piperazinyl]ethyl}-5-isoquinolinesulfonamide.

IR (KBr) cm⁻¹ : 1610, 1510, 1445, 1320, 1150, 1130, 993;

¹ H-NMR (CDCl₃, δ ppm): 2.00-2.20 (4H, m), 2.26 (1H, dd, J=5.9, 12.7Hz), 2.36 (1H, dd, J=7.8, 12.7 Hz), 2.46-2.60 (2H, m), 2.62-2.77 (2H, m)2.83-3.00 (2H, m), 3.00-3.41 (5H, m), 5.24 (1H, br), 6.43 (2H, d, J=8.3Hz), 6.71 (2H, d, J=8.3 Hz), 7.13-7.34 (5H, m), 7.69 (1H, dd, J=7.3, 8.3Hz), 8.20 (1H, d, J=7.8 Hz), 8.34 (1H, d, J=5.9 Hz), 8.40 (1H, dd,J=1.0, 7.3 Hz), 8.63 (1H, br), 9.12 (1H, br).

EXAMPLE 70

The same procedure as described in Example 68 was repeated except thatphenylisocyanate was used in place of benzyl chloroformate, to obtainN-[1-(p-hydroxybenzyl)-2-(4-phenylaminocarbonylpiperazinyl)ethyl]-5isoquinolinesulfonamidein yellow amorphous form.

1H-NMR (CDCl₃ +CD₃ OD, δ ppm): 2.37 (1H, dd, J=8.8, 14.2 Hz), 2.65 (1H,dd, J=5.4, 13.7 Hz), 2.73-3.20 (4H, m), 3.40-3.95 (7H, m), 6.12 (2H, d,J=8.3 Hz), 6.50 (2H, d, J=8.3 Hz), 7.05 (1H, m), 7.25-7.38 (4H, m), 7.67(1H, dd, J=7.8, 8.3 Hz), 8.21 (1H, d, J=7.8 Hz), 8.31 (1H, d, J=6.8 Hz),8.53 (1H, br), 9.23 (1H, br).

EXAMPLE 71

The same procedure as described in Example 68 was repeated except thatbenzylisocyanate was used in place of benzyl chloroformate, to obtainN-[2-(4-benzylaminocarbonylpiperazinyl)-1-(p-hydroxybenzyl)ethyl]-5-isoquinolinesulfonamide in a yellow amorphous form.

¹ H-NMR (CDCl₃ --CD₃ OD, δ ppm): 2.40-2.71 (2H, m), 2.76-3.23 (4H, m),3.40-3.80 (7H, m), 4.39 (2H, s), 6.08 (2H, d, J=8.3 Hz), 6.46 (2H, d,J=8.3 Hz), 7.20-7.38 (5H, m), 7.63 (1H, t, J=7.8 Hz), 8.17 (1H, d, J=8.3Hz), 8.29 (2H, d, J=6.9 Hz), 8.52 (1H, br), 9.23 (1H, br).

EXAMPLE 72

200 mg of the amorphous compound obtained in Example 67 was dissolved in5 ml of chloroform, and to the solution was added 1 ml of methanol, andalso a solution of diazomethane in ether with ice cooling. The reactionmixture was stirred for 90 minutes and then concentrated. Resultingresidue was applied to silica gel column and eluted withchloroform/methanol (80:1 to 50:1), to obtain 103 mg ofN-[2-(4-benzyloxycarbonylpiperazinyl)-1-(p-methoxybenzyl)ethyl]-N-methyl-5-isoquinolinesulfonamide.

IR (KBr) cm⁻¹ : 1692, 1508, 1420, 1320, 1235, 1120;

¹ H-NMR (CDCl₃, δ ppm): 2.32-2.45 (5H, m), 2.53-2.65 (2H, m), 2.78-2.90(1H, m) 2.92 (3H, s), 3.37 (4H, m), 3.73 (3H, s), 4.16 (1H, m), 5.11(2H, s), 6.50 (2H, d, J=8.3 Hz) 6.82 (2H, d, J=8.3 Hz), 7.35 (5H, s),7.55 (1H, t, J=7.8 Hz), 8.09 (1H, d, J=8.3 Hz), 8.18 (1H, d, J=6.4 Hz),8.22 (1H, d, J=7.3 Hz), 8.55 (1H, d, J=6.4 Hz), 9.24 (1H, s).

EXAMPLE 73

The product of Example 68 was treated according to the procedure inExample 72, to obtainN-[2-(4-benzyloxycarbonylpiperazinyl)-1-(p-methoxybenzyl)ethyl]-5-isoquinolinesulfonamide.

¹ H-NMR (CDCl₃, δ ppm): 1.97-2.17 (4H, m), 2.19 (1H, dd, J=4.4, 13.7Hz), 2.28 (1H, dd, J=6.8, 13.7 Hz), 2.70 (1H, dd, J=6.8, 14.2 Hz), 2.82(1H, dd, J=5.4, 14.2 Hz), 3.03 (2H, m), 3.15 (2H, m), 3.34 (1H, m), 3.74(3H, s), 5.07 (2H, s), 5.36 (1H, br), 6.59 (2H, d, J=8.8 Hz), 6.85 (2H,d, J=8.3 Hz), 7.27-7.37 (5H, m), 7.68 (1H, dd, J=7.3, 7.8 Hz), 8.18 (1H,d, J=8.3 Hz), 8.39 (1H, d, J=5.9 Hz), 8.42 (1H, dd, J=1.0, 7.8 Hz), 8.67(1H, d, J=5.9 Hz), 9.33 (1H, s).

EXAMPLE 74N-{2-(4-Benzoylpiperazinyl)-1-[p-(5-isoquinolinesulfonyloxy)benzyl]ethyl}-N-methyl-5-isoquinolinesulfonamide

764 mg of the intermediate crystals obtained in Example 61 was suspendedin 7 ml of tetrahydrofuran, to the suspension were added 135 mg ofbenzoyl chloride and 5 minutes later 1.1 ml of triethylamine with icecooling, and the mixture was stirred for one hour. After addingchloroform and water, the reaction mixture was extracted three timeswith 30 ml of chloroform, and the extract was washed with saturatedsodium chloride aqueous solution, dried over magnesium sulfate andconcentrated to dryness under a reduced pressure. 0.82 g of theresulting pale yellow residue was applied to a silica gel column andeluted with chloroform/methanol (100:1) to obtain 198 mg of the titlecompound in a colorless amorphous form.

IR (KBr) cm⁻¹ : 1620, 1370, 1130;

¹ H-NMR (CDCl₃, δ ppm): 2.2-2.8 (10H, m), 2.84 (3H, s), 3.1-3.7 (4H, m),4.14 (1H, m), 6.61 (2H, d, J=8.6 Hz), 6.85 (2H, d, J=8.6 Hz), 7.3-8.6(14H, m), 8.84 (1H, d, J=5.8 Hz), 9.30 (1H, s), 9.43 (1H, s).

EXAMPLE 75N-2-(4-Benzoylpiperazinyl)-1-(p-hydroxybenzyl)ethyl]-N-methyl-5-isoquinolinesulfonamide

To 349 mg of the amorphous compound obtained in Example 74 were added 4ml of methanol, 1 ml of tetrahydrofuran and 0.5 ml of 2N sodiumhydroxide, and after refluxing for 2 hours, to the reaction mixture wereadded chloroform, water and sodium chloride. The reaction mixture wasthree times extracted with 30 ml of chloroform, and the extract waswashed with saturated sodium chloride aqueous solution, dried overmagnesium sulfate and concentrated under a reduced pressure to obtain0.25 g of yellow oil. The yellow oil was applied to a silica gel columnand eluted with chloroform/methanol (50:1) to obtain 145 mg of the titlecompound in a colorless amorphous form.

IR (KBr) cm⁻¹ : 1610, 1440, 1120;

¹ H-NMR (CDCl₃, δ ppm): 2.6-2.9 (8H, m), 2.99 (3H, s), 3.2-3.9 (4H, m),4.00 (1H, m), 6.25 (2H, d, J=8.5 Hz), 6.56 (2H, d, J=8.5 Hz), 7.41 (5H,s), 7.59 (1H, t, J=7.9 Hz), 8.08 (1H, d, J=6.1 Hz), 8.15 (1H, d, J=7.9Hz), 8.25 (1H, d, J=7.9 Hz), 8.46 (1H, d, J=6.1 Hz), 9.29 (1H, s)

EXAMPLE 76

The same procedures as described in Examples 74 and 75 were sequentiallyrepeated except that 470 mg of the intermediate crystals in Example 61and 113 mg of benzylsulfonyl chloride in place of benzoyl chloride wereused to obtain 116 mg ofN-[2-(4-benzylsulfonylpiperazinyl)-1-(p-hydroxybenzyl)ethyl]-N-methyl-5-isoquinolinesulfonamidein a colorless amorphous form.

IR (KBr) cm⁻¹ : 1610, 1320, 1150;

¹ H-NMR (CDCl₃, δ ppm): 2.3-2.9 (8H, m), 2.94 (3H, s), 3.0-3.2 (4H, m),4.03 (1H, m), 4.20 (2H, s), 6.26 (2H, d, J=8.2 Hz), 6.56 (2H, d, J=8.2Hz), 7.40 (5H, s), 7.60 (1H, t, J=7.9 Hz), 8.07 (1H, d, J=6.4 Hz), 8.15(1H, d, J=7.9 Hz), 8.22 (1H, d, J=7.9 Hz), 8.46 (1H, d, J=6.4 Hz), 9.29(1H, s).

EXAMPLE 77

The same procedures as described in Examples 74 and 75 were sequentiallyrepeated except that 382 mg of the intermediate crystals in Example 61and 133 mg of 5-isoquinolinesulfonamide.HCl in place of benzoyl chloridewere used, to obtainN-{1-(p-hydroxybenzyl]-2-[4-(5-isoquinolinesulfonyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamide in a colorless amorphous form.

IR (KBr) cm⁻¹ : 1610, 1320, 1150;

¹ H-NMR (CDCl₃, δ ppm): 2.3-2.8 (8H, m), 2.90 (3H, s), 3.0-3.2 (4H, m),3.95 (1H, m), 6.29 (2H, d, J=8.6 Hz), 6.53 (2H, d, J=8.6 Hz), 7.50 (1H,t, J=7.9 Hz), 7.75 (1H, t, J=7.9 Hz), 8.0-8.1 (2H, m), 8.17 (1H, d,J=7.9 Hz), 8.26 (1H, d, J=7.9 Hz), 8.3-8.5 (2H, m), 8.53 (1H, d, J=6.1Hz), 8.70 (1H, d, J=6.1 Hz), 9.19 (1H, s), 9.39 (1H, s).

EXAMPLE 78

The same procedures as described in Examples 59 and 60 were sequentiallyrepeated except that α-naphtharenesulfonyl chloride was used in place of5-isoquinolinesulfonyl chloride.HCl, to obtainN-{2-(4-benzyloxycarbonylpiperazinyl)-1-[p-(α-naphtharenesulfonyloxy)benzyl]ethyl}-N-methyl-α-naphtharenesulfonamidein a colorless amorphous form.

IR (KBr) cm⁻¹ : 1700, 1365, 1130, 860, 765;

¹ H-NMR (CDCl₃, δ ppm): 2.05-2.25 (5H, m), 2.41 (1H, dd, J=13.13, 6.85Hz), 2.55-2.8 (2H, m), 2.84 (3H, s), 3.05-3.25 (4H, m), 4.05 (1H,quintet, J=6.85 Hz), 5.11 (2H, s), 6.57 (2H, d, J=8.57 Hz), 6.82 (2H, d,J=8.57 Hz), 7.25-7.60 (9H, m), 7.60-8.20 (8H, m), 8.42 (1H, m), 8.82(1H, d, J=7.99 Hz).

EXAMPLE 79

The amorphous compound obtained in Example 78 was subjected to alkalinehydrolysis according to the procedure in Example 62 to obtainN-[2-(4-benzyloxycarbonylpiperazinyl)-1-(p-hydroxybenzyl)ethyl]-N-methyl-.alpha.-naphtharenesulfonamidein a colorless amorphous form.

IR (KBr) cm⁻¹ : 1695, 1670, 1310, 1240, 1120;

¹ H-NMR (CDCl₃, δ ppm): 2.15-2.4 (5H, m), 2.48 (1H, dd, J=12.56, 7.42Hz), 2.6-2.85 (2H, m), 2.87 (3H, s), 3.15-3.35 (4H, m), 4.20 (1H,quintet, J=6.85 Hz), 5.10 (2H, s), 5.13 (1H, br), 6.58 (2H, d, J=7.99Hz), 6.89 (2H, d, J=7.99 Hz), 7.33 (5H, s), 7.44 (1H, t, J=7.42 Hz),7.47-7.63 (2H, m), 7.8-7.93 (1H, m), 7.99 (1H, d, J=7.99 Hz), 8.15 (1H,dd, J=6.85, 1.0 Hz), 8.45-8.6 (1H, m).

EXAMPLE 80 N-{1-[p-(5-Isoquinolinesulfonyloxy)benzyl-2-(4-phenylhomopiperazinyl)ethyl}-5-isoquinolinesulfonamide

The same procedure as described in Example 34 except that1-[2-amino-3-(p-hydroxyphenyl)propyl]-4-phenylhomopiperazine was used inplace of 1-[2-amino-3-(p-hydroxyphenyl)propyl]-4-phenylpiperazine, toobtain the title compound in a yellow amorphous form.

IR (KBr) cm⁻¹ : 1620, 1600, 1365, 1135;

¹ H-NMR (CDCl₃, δ ppm): 2.10-2.36 (7H, m), 2.63 (1H, dd, J=6.8, 13.7Hz), 2.76 (1H, dd, J=4.9, 13.7 Hz), 2.99-3.29 (6H, m), 6.53 (2H, d,J=8.3 Hz), 6.60 (2H, d, J=8.8 Hz), 6.64 (1H, t, J=7.3 Hz), 6.80 (2H, d,J=8.8 Hz), 7.17 (1H, t, J=8.8 Hz), 7.62 (1H, t, J=7.8 Hz), 7.66 (1H, t,J=7.8 Hz), 8.18 (1H, d, J=8.3 Hz), 8.26 (2H, d, J=7.3 Hz), 8.37-8.38(2H, m), 8.53 (1H, d, J=5.9 Hz), 8.67 (1H, d, J=6.4 Hz), 8.82 (1H d, J=5.9 Hz), 9.33 (1H, s), 9.42 (1H, s).

EXAMPLE 81

The amorphous compound obtained in Example 80 was treated with methyliodide according to the procedure in Example 35 to obtainN-{1-[p-(5-isoquinolinesulfonyloxy)benzyl]-2-(4-phenylhomopiperazinyl)ethyl}-N-methyl-5-isoquinolinesulfonamidein a yellow amorphous form.

IR (KBr) cm⁻¹ : 1620, 1600, 1500, 1365, 1135;

¹ H-NMR (CDCl₃, δ ppm): 1.70 (2H, m), 2.37 (1H, dd, J=8.8, 11.7 Hz),2.40-2.65 (6H, m), 2.76 (1H, dd, J=4.9, 13.7 Hz), 2.84 (3H, s),3.23-3.42 (4H, m), 3.98 (1H, m), 6.51-6.65 (5H, m), 6.77 (2H, d, J=8.3Hz), 7.16 (2H, t, J=7.8 Hz), 7.54 (1H, dd, J=7.3, 8.3 Hz), 7.59 (1H, t,J=7.8 Hz), 8.08 (1H, d, J=7.8 Hz), 8.18-8.26 (4H, m), 8.55 (1H, d, J=5.9Hz), 8.55 (1H, dd, J=1.0, 6.3 Hz), 8.84 (1H, d, J=6.3 Hz), 9.26 (1H, s),9.41 (1H, d, J=1.0 Hz).

The amorphous compounds obtained in Examples 80 and 81 were subjected toalkaline hydrolysis according to the procedure described in Example 36,to obtain the following two compounds.

EXAMPLE 82N-[1-(p-Hydroxybenzyl)-2-(4-phenylhomopiperazinyl)ethyl]-5-isoquinolinesulfonamide

Yellow crystals;

Melting point: 170°-178° C. (decomposed);

IR (KBr) cm⁻¹ : 1615, 1600, 1505, 1365, 1320, 1205, 1155, 1130;

¹ H-NMR (CDCl₃, δ ppm): 1.79 (2H, m), 2.44 (1H, dd, J=8.3, 13.7 Hz),2.50-2.72 (7H, m), 3.23 (1H, m), 3.30-3.45 (4H, m), 6.24 (2H, d, J=8.3Hz), 6.51 (2H, d, J=8.3 Hz), 6.66 (2H, d, J=8.3 Hz), 6.68 (1H, t, J=7.3Hz), 7.23 (2H, dd, J=7.3, 8.3 Hz), 7.64 (1H, t, J=7.8 Hz), 8.19 (1H, d,J=7.8 Hz), 8.27 (1H, d, J=6.4 Hz), 8.34 (1H, dd, J=1.0, 7.3 Hz), 8.53(1H, d, J=6.4 Hz), 9.33 (1H, brs).

EXAMPLE 83N-[1-(p-Hydroxybenzyl)-2-(4-phenylhomopiperazinyl)ethyl]-N-methyl-5-isoquinolinesulfonamide

Yellow amorphous.

IR (KBr) cm⁻¹ : 1615, 1600, 1500, 1360, 1320, 1210, 1150, 1125;

¹ H-NMR (CDCl₃, δ ppm): 1.93 (2H, m), 2.40 (1H, dd, J=9.8, 14.2 Hz),2.56 (1H, dd, J=8.8, 12.7 Hz), 2.70 (2H, m), 2.80-2.92 (4H, m), 3.00(3H, s), 3.46-3.53 (4H, m), 3.85 (1H, m), 6.19 (2H, d, J=8.3 Hz), 6.51(2H, d, J=8.3 Hz), 6.65 (1H, t, J=7.3 Hz), 6.69 (2H, d, J=8.3 Hz), 7.21(2H, dd, J=7.3, 8.8 Hz), 7.58 (2H, t, J=7.3 Hz), 8.07 (1H, d, J=6.4 Hz),8.12 (1H, d, J=8.3 Hz), 8.27 (1H, dd, J=1.0, 7.3 Hz), 8.45 (1H, d, J=5.9Hz), 9.27 (1H, s)

REFERENCE EXAMPLE 18 N-tert-Butoxvcarbonvl-4-hydroxypiperidine

7.14 g of 4-piperidone.monohydrate.hydrochloride was dissolved in 50 mlof dimethylformamide and 10 ml of water, and to the solution were added25 ml of diisopropylethylamine and 9.5 g of di-tert-butyl dicarbonate ata room temperature with stirring, and the reaction mixture was stirredfor 4 hours. After adding water and saturating with sodium chloride, thereaction mixture was extracted twice with 300 ml of chloroform. Theextract was dried over magnesium sulfate and evaporated under a reducedpressure to obtain 9.6 g of residue, which was then dissolved in 100 mlof ethanol. To the solution was added 1.83 g of sodium borohydride withstirring under ice cooling, and the mixture was stirred for 90 minutesunder the same condition, and then for 30 minutes at a room temperature.After adding saturated sodium chloride aqueous solution, the reactionmixture was alkalized with sodium bicarbonate and extracted twice with600 ml of chloroform. The extract was dried over magnesium sulfate andevaporated under a reduced pressure, and resulting residue was subjectedto a silica gel column and eluted with hexane/ethyl acetate (2:1), toobtain 8.03 g of the title compound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.35-1.6 (2H, m), 1.45 (9H, s), 1.75-1.95 (2H,m), 3.03 (2H, ddd, J=13.13, 10.28, 4.00 Hz), 3.75-3.95 (3H, m).

REFERENCE EXAMPLE 19 4-(p-Methylbenzyloxy)piperidine

2.0 g of the amorphous compound obtained in Reference Example 18 wasdissolved in 20 ml of dimethylformamide, to the solution was added 0.48g of 60% sodium hydride in an ice bath. After removing from the icebath, the reaction mixture was stirred at a room temperature for 30minutes, and after adding 1.54 g of p-methylbenzyl chloride, furtherstirred for 18 hours. The reaction mixture was poured on ice, saturatedwith sodium chloride and extracted twice with 150 ml of chloroform. Theextract was dried over magnesium sulfate and evaporated under a reducedpressure, and resulting residue was applied to a silica gel column andeluted with hexane/ethyl acetate (5:1) to obtain 1.27 g ofN-tert-butoxycarbonyl-4-p-methylbenzyloxypiperidine. This compound wasdissolved in 3 ml of ethyl acetate, and after adding 12 ml of 3Nhydrogen chloride in ethyl acetate at a room temperature with furtherstirring for 17 hours, the solvent was evaporated off under a reducedpressure. Resulting residue was dissolved in water, and the solution wasalkalized with sodium bicarbonate, saturated with sodium chloride andextracted twice with 200 ml of chloroform. The extract was dried overmagnesium sulfate and the solvent was evaporated off under a reducedpressure to obtain 830 mg of the title compound in colorless amorphousform.

¹ H-NMR (CDCl₃, δ ppm): 1.55-1.8 (2H, m), 1.9-2.15 (2H, m), 2.34 (3H,s), 2.81 (2H, ddd, J=13.13, 10.28, 4.00 Hz), 3.17 (2H, ddd, J=11.42,7.42, 4.00 Hz), 3.56 (1H, septet, J=3.71 Hz), 4.50 (2H, s), 5.01 (1H,brs), 7.14 (2H, d, J=7.99 Hz), 7.22 (2H, d, J=7.99 Hz).

REFERENCE EXAMPLE 20N-tert-Butoxycarbonyl-o-(2-methoxyethoxymethyl)tyrosine methyl ester

13.39 g of N-tert-butoxycarbonyltyrosine methyl ester was dissolved in65 ml of tetrahydrofuran and 65 ml of dimethylformamide, and to thesolution was added 1.9 g of 60% sodium hydride with stirring in an icebath. After removing from the ice bath, the mixture was stirred at aroom temperature for 30 minutes, and after addition of 5.4 g ofmethoxyethoxymethyl chloride with ice cooling, stirred for 15 hoursallowing to warm to a room temperature. The reaction mixture was pouredon ice, saturated with sodium chloride and extracted twice with 800 mlof chloroform. The extract was dried over magnesium sulfate and thesolvent was evaporated under a reduced pressure, and resulting residuewas applied to a silica gel column and eluted with hexane/ethyl acetate(4:1) to obtain 13.85 g of the title compound in a colorless amorphousform.

¹ H-NMR (CDCl₃, δ ppm): 1.46 (9H, s), 3.02 (2H, m), 3.37 (3H, s),3.5-3.6 (2H, m), 3.71 (3H, s), 3.75-3.85 (2H, m), 4.54 (1H, m), 4.95(1H, m), 5.24 (2H, s), 6.96 (2H, d, J=9.71 Hz), 7.04 (2H, d, J=9.71 Hz).

REFERENCE EXAMPLE 212-(N-tert-Butoxycarbonylamino)-1-chloro-3-[p-(2-methoxyethoxymethoxy)phenyl]propane

13.85 g of the amorphous compound obtained in Reference Example 20 wasdissolved in 90 ml of ethanol and 60 ml of tetrahydrofuran, and to thesolution were added 3.11 g of lithium chloride and 2.77 g of sodiumborohydride with stirring in an ice bath. After removing from the icebath, the mixture was stirred at a room temperature for 16 hours, andafter addition of satulated sodium chloride aqueous solution, thereaction mixture was alkalized with sodium bicarbonate and extractedtwice with 800 ml of chloroform. The extract was dried over magnesiumsulfate and the solvent was evaporated off under a reduced pressure, toobtain 11.73 g ofN-tert-butoxycarbonyl-o-(2-methoxyethoxymethyl)tyrosinol. This compoundwas dissolved in 120 ml of of carbon tetrachloride, and to the solutionwas added 10 g of triphenylphosphine. The mixture was refluxed for 3hours and further heated at 80° C. for 17 hours. The solvent wasevaporated off under a reduced pressure, and the resulting residue wasapplied to a silica gel column and eluted with chloroform/methanol(100:1) followed by with hexane/ethyl acetate (4:1), to obtain 7.22 g ofthe title compound in colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.43 (9H, s), 2.75-2.9 (2H, m), 3.38 (3H, s),3.4-3.65 (4H, m), 3.75-3.9 (2H, m), 4.08 (1H, m), 4.79 (1H, m), 5.26(2H, s), 6.99 (2H, d, J=9.71 Hz), 7.16 (2H, d, J=9.71 Hz).

REFERENCE EXAMPLE 22N-{2-(tert-Butoxycarbonylamino)-3-[p-(2-methoxyethoxymethoxy)phenyl]propyl)-4-(p-methylbenzyloxy)piperidine

1.56 g of the amorphous compound obtained in Reference Example 21 wasdissolved in 25 ml of dimethylformamide, to the solution were added 0.83g of the amorphous compound obtained in Reference Example 19, 0.67 g ofpotassium carbonate and 0.67 g of sodium iodide, and the mixture wasstirred at 100° C. for 2 hours, and after adding saturated sodiumchloride aqueous solution, extracted twice with 150 ml of chloroform.The extract was dried over magnesium sulfate and the solvent wasevaporated off under a reduced pressure. Resulting residue was appliedto a silica gel column and eluted with chloroform/methanol (100:1) toobtain 490 mg of the title compound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.42 (9H, s), 1.5-1.75 (3H, m), 1.75-2.0 (2H,m), 2.0-2.3 (3H, m), 2.33 (3H, s), 2.55-2.95 (4H, m), 3.25-3.5 (1H, m),3.38 (3H, s), 3.5-3.65 (2H, m), 3.75-3.95 (3H, m), 4.49 (2H, s), 4.64(1H, m), 5.25 (2H, s), 6.96 (2H, d, J=9.71 Hz), 7.09 (2H, d, J=9.71 Hz),7.14 (2H, d, J=9.71 Hz), 9.23 (2H, d, J=9.71 Hz).

EXAMPLE 84N-{1-p-(5-Isoquinolinesulfonyloxy)benzyl]-2-4-(p-methylbenzyloxy)piperidino]ethyl}-5-isocuinolinesulfonamide

490 mg of the amorphous compound obtained in Reference Example 22 wasdissolved in 1 ml of ethyl acetate, and to the solution was added 5 mlof 3N hydrogen chloride in ethyl acetate at a room temperature withstirring, and the reaction mixture was stirred for one-hour. Afterevaporating off the solvent, resulting residue was alkalized with sodiumbicarbonate aqueous solution, and the mixture was saturated with sodiumchloride, washed with a small amount of methanol, and extracted twicewith 100 ml of chloroform. The extract was dried over magnesium sulfate,and the solvent was evaporated off to obtain a residue comprisingN-[2-amino-3-(p-hydroxyphenyl)]propyl-4-(p-methylbenzyloxy)piperidine.The residue was dissolved in 7 ml of tetrahydrofuran, and to thesolution were added 545 mg of 5-isoquinolinesulfonyl chloride.HCl and450 mg of triethylamine at a room temperature with stirring. Thereaction mixture was stirred for 18 hours, alkalized with a sodiumbicarbonate aqueous solution and extracted twice with 100 ml ofchloroform. The extract was dried over magnesium sulfate, and thesolvent was evaporated off under a reduced pressure, and resultingresidue was applied to a silica gel column and eluted withchloroform/methanol (30:1) to obtain 572 mg of the title compound incolorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.0-1.33 (3H, m), 1.33-1.54 (1H, m), 1.59-1.88(2H, m), 1.88-2.25 (4H, m), 2.33 (3H, s), 2.71 (1H, dd, J=14.28, 6.85Hz), 2.91 (1H, dd, J=14.28, 4.57 Hz), 3.18 (2H, m), 4.34 (2H, s), 6.68(2H, d, J=9.14 Hz), 6.90 (2H, d, J=9.14 Hz), 7.14 (4H, s), 8.13 (1H, t,J=7.42 Hz), 8.18 (1H, t, J=7.42 Hz), 9.19 (1H, d, J=7.42 Hz), 8.27 (2H,d, J=7.42 Hz), 8.40 (1H, dd, J=7.99, 1.0 Hz), 8.44 (1H, d, J=6.85 Hz),8.52 (1H, d, J=6.28 Hz), 8.68 (1H, d, J=6.28 Hz), 8.81 (1H, d, J=6.28Hz), 9.34 (1H, s), 9.41 (1H, s).

EXAMPLE 85N-{1-(p-Hydroxybenzyl)-2-4-(p-methylbenzyloxy)piperidino]ethyl}-isoquinolinesulfonamide

400 mg of the amorphous compound obtained in Example 84 was dissolved in2.5 ml of methanol and 2.5 ml of tetrahydrofuran, to the solution wasadded 4 ml of 1N sodium hydroxide solution, and the mixture was refluxedfor 2 hours. After cooling, the reaction mixture was diluted with water,acidified with citric acid and then alkalized with sodium bicarbonate,and extracted twice with 100 ml of chloroform. The extract was driedover magnesium sulfate, and the solvent was evaporated off under areduced pressure. Resulting residue was applied to a silica gel columnand eluted with chloroform/methanol (20:1) to obtain 172 mg of the titlecompound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.2-1.75 (4H, m), 1.85-2.15 (2H, m), 2.2-2.58(4H, m), 2.32 (3H, s), 2.58-2.85 (2H, m), 3.15-3.4 (2H, m), 4.41 (2H,s), 4.8 (2H, br), 6.42 (2H, d, J=9.14 Hz), 6.68 (2H, d, J=9.14 Hz), 7.14(2H, d, J=7.42 Hz), 7.19 (2H, d, J=7.42 Hz), 7.67 (1H, t, J=7.42 Hz),8.19 (1H, d, J=7.42 Hz), 8.33-8.50 (2H, m), 8.58 (1H, d, J=6.28 Hz),9.33 (1H, s).

EXAMPLE 86

The same procedure as described in Example 84 was repeated except thatN-{2-(tert-butoxycarbonylamino)-3-[p-(2-methoxyethoxymethoxy)phenyl]propyl}-4-(3,4-dichlorobenzyloxy)piperidinewas used in place ofN-{(2-(tertbutoxycarbonylamino)-3-[p-(2-methoxyethoxymethoxy)phenyl]propyl}-4-(p-methylbenzyloxy)piperidine,to obtainN-{1-[p-5-isoquinolinesulfonyloxy)benzyl]-2-[4-(3,4-dichlorobenzyloxy)piperidino]ethyl}-5-isoquinolinesulfonamide in a colorless amorphousform.

¹ H-NMR (CDCl₃, δ ppm): 0.95-1.17 (1H, m), 1.17-1.34 (2H, m), 1.34-1.91(2H, m), 1.91-2.30 (4H, m), 2.72 (1H, dd, J=13.13, 7.42 Hz), 2.89 (1H,dd, J=13.13, 4.57 Hz), 3.20 (2H, m), 4.33 (2H, s), 6.68 (2H, d, J=9.14Hz), 6.92 (2H, d, J=9.14 Hz), 7.10 (1H, dd, J=9.14, 1.71 Hz), 7.36 (1H,d, J=1.71 Hz), 7.38 (1H, d, J=9.14 Hz), 7.64 (1H, t, J=7.42 Hz), 7.68(1H, t, J=7.42 Hz), 8.20 (1H, d, J=7.42 Hz), 8.28 (2H, d, J=7.42 Hz),8.39 (1H, dd, J= 7.42, 1.0 Hz), 8.43 (1H, d, J=6.28 Hz), 8.53 (1H, d,J=6.28 Hz), 8.69 (1H, d, J=6.28 Hz), 8.80 (1H, d, J=6.28 Hz), 9.35 (1H,s), 9.42 (1H, s);

IR (KBr) cm⁻¹ : 1615, 1375, 1130, 860.

EXAMPLE 87

The amorphous compound obtained in Example 86 was subjccted to alkalinehydrolysis according to the procedure in Example 85, to obtainN-{1-(p-hydroxybenzyl)-2-4-(3,4-dichlorobenzyloxy)piperidino]ethyl}-5-isoquinolinesulfonamide in a colorless amorphous form.

IR (KBr) cm⁻¹ : 1615, 1375, 1130, 860;

¹ H-NMR (CDCl₃, δ ppm): 1.2-1.8 (4H, m), 1.9-2.2 (2H, m), 2.2-2.6 (4H,m), 2.62 (1H, dd, J=14.28, 6.85 Hz), 2.75 (1H, dd, J=14.28, 6.28 Hz),3.29 (2H, m), 4.33 (2H, br), 4.39 (2H, s), 6.38 (2H, d, J=8.57 Hz), 6.67(2H, d, J=8.57 Hz), 7.12 (1H, dd, J=8.57, 1.71 Hz), 7.38 (1H, d, J=8.57Hz), 7.39 (1H, d, J=1.71 Hz), 7.67 (1H, t, J=7.42 Hz), 8.20 (1H, d,J=7.42 Hz), 8.37 (1H, d, J=6.28 Hz), 8.40 (1H, dd, J=7.42, 1.0 Hz), 8.58(1H, d, J= 6.28 Hz), 9.32 (1H, s).

REFERENCE EXAMPLE 23

The same procedure as described in Reference Example 21 was repeated,except that N-benzyloxycarbonyl-o-benzyltyrosine methyl ester was usedin place of N-tert-butoxycarbonyl-o-(2-methoxyethoxymethyl)tyrosinemethyl ester, to obtain2-benzyloxycarbonylamino-3-(p-benzyloxyphenyl)-1-chloropropane incolorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 2.7-2.95 (2H, m), 3.49 (1H, dd, J=11.42, 3.43Hz), 3.63 (1H, dd, J=11.42, 4.00 Hz), 4.13 (1H, m), 5.00 (1H, m), 5.04(2H, s), 5.10 (2H, s), 6.92 (2H, d, J=7.99 Hz), 7.15 (2H, d, J=7.99 Hz),7.3-7.5 (5H, m).

To the amorphous compound so obtained was added N-phenylpiperazine, andthe same procedure as described in Reference Example 21 was repeated toobtain1-{2-(benzyloxycarbonylamino)-3-(p-Benzyloxyphenyl)propyl}-4-phenylpiperazinein a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 2.34 (2H, d, J=6.85 Hz), 2.4-2.7 (4H, m),2.75-3.0 (2H, m), 3.14 (4H, t, J=5.14 Hz), 3.99 (1H, m), 4.90 (1H, m),5.04 (2H, s), 5.10 (2H, s), 6.75-7.0 (5H, m), 7.09 (2H, d, J=8.57 Hz),7.2-7.5 (12H, m).

EXAMPLE 88N-{1-(p-Benzyloxy)benzyl]-2-(4-phenylpiperazinyl)ethyl)-5-isoquinolinesulfonamide

500 mg of the 1-substituted 4-phenylpiperazine obtained in ReferenceExample 23 was dissolved in 1 ml of acetic acid, and to the solution wasadded 2 ml of 30% hydrogen bromide in acetic acid, and the mixture wasstirred for 10 minutes and poured on ice. After adding saturated sodiumthiosulfate aqueous solution, the reaction mixture was alkalized withsaturated sodium bicarbonate aqueous solution, and extracted twice with150 ml of chloroform. The extract was dried over magnesium sulfate andthe solvent was evaporated off under a reduced pressure, and resultingresidue was applied to a silica gel column and eluted withchloroform/methanol (30:1), to obtain 235 mg of1-{2-amino-3-(p-benzyloxyphenyl)propyl}-4-phenylpiperazine. 235 mg ofthis compound was dissolved in 5 ml of tetrahydrofuran, and to thesolution were added 195 mg of 5-isoquinolinesulfonyl chloride.HCl and178 mg of triethylamine at a room temperature with stirring, and themixture was stirred for 16 hours. After adding saturated sodium chlorideaqueous solution, the reaction mixture was alkalized with sodiumbicarbonate aqueous solution, and extracted twice with 150 ml ofchloroform. The extract was dried over magnesium sulfate, and thesolvent was evaporated off under a reduced pressure, and resultingresidue was applied to a silica gel column and eluted withchloroform/methanol (50:1) to obtain 280 mg ofN-{1-[(4-benzyloxy)benzyl]-2-(4-phenylpiperazinyl)ethyl}-5-isoquinolinesulfonamidein a calorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 2.1-2.5 (6H, m), 2.7-3.0 (6H, m), 3.37 (1H, m),4.99 (2H, s), 5.5 (1H, br), 6.71 (2H, d, J=8.57 Hz), 6.81 (3H, t, J=8.57Hz), 6.90 (2H, d, J=8.57 Hz), 7.24 (2H, t, J=8.57 Hz), 7.3-7.5 (5H, m),7.68 (1H, t, J=7.42 Hz), 8.17 (1H, d, J=7.99 Hz), 8.43 (1H, d, J=6.28Hz), 8.46 (1H, d,J=6.85 Hz), 8.67 (1H, d, J=6.28 Hz), 9.32 (1H, s).

EXAMPLE 89 N-{2-[4-(3,4-Dichlorobenzyloxy)piperidino]-1-[p-(5-isoquinolinesulfonyloxy)benzyl]ethyl}-N-methyl-5-isoquinolinesulfonamide

1.70 g of the amorphous compound obtained in Example 86 was dissolved in10 ml of dimethylformamide, and to the solution was added 93 mg ofsodium hydride with stirring in an ice bath, and after stirring for 10minutes the ice bath was removed. The reaction mixture was stirred at aroom temperature for 4 hours, and after adding 150 ml of ethyl acetate,washed three times with water and the washing were extracted with 50 mlof ethyl acetate. The extracts were combined and washed with saturatedsodium chloride aqueous solution, dried over magnesium sulfate, and thesolvent was evaporated off under a reduced pressure. Resulting residuewas applied to a silica gel column (silica gel: Fuji Debison Kagaku,BW-820MH), and eluted with 1% methanol in chloroform to obtain 1.30 g ofthe title compound in a colorless amorphous form.

IR (CHCl₃) cm⁻¹ : 2920, 2810, 1618, 1583, 1563, 1450, 983, 902;

¹ H-NMR (CDCl₃, δ ppm): 1.30-1.52 (2H, m), 1.60-1.78 (2H, m), 1.95-2.12(2H, m), 2.15-3.00 (6H, m), 2.84 (3H, s), 3.31 (1H, m), 4.10 (1H, m),4.42 (2H, s), 6.58 (2H, brd, J=8.5 Hz), 6.87 (2H, brd, J=8.5 Hz), 7.14(1H, dd, J=8.3, 1.9 Hz), 7.39 (1H, d, J=8.3 Hz), 7.41 (1H, d, J=1.9 Hz),7.53-7.65 (2H, m), 8.11 (1H, d, J=8.3 Hz), 8.28-8.31 (3H, m), 8.32 (1H,dd, J=7.5, 1.2 Hz), 8.54 (1H, brd, J=6.1 Hz), 8.57 (1H, d, J=6.1 Hz),8.83 (1H, d, J=6.1 Hz), 9.28 (1H, d, J=1.0 Hz), 9.41 (1H, d, J=1.0 Hz).

EXAMPLE 90N-{2-[4-(3,4-Dichlorobenzyloxy)piperidino]-1-(p-hydroxybenzyl)ethyl)-N-methyl-5-isoquinolinesulfonamide

1.04 g of the amorphous compound obtained in Example 89 was dissolved in10 ml of dimethylsulfoxide, to the solution was added a solution of 152mg of sodium hydroxide in 2 ml of water, and the mixture was stirred at80° C. for 2 hours. After adding 150 ml of ethyl acetate, the reactionmixture was twice washed with 100 ml of water, and the washings wereextracted with 50 ml of ethyl acetate. The ethyl acetate layers werecombined, washed with saturated sodium chloride aqueous solution, driedover magnesium sulfate and evaporated to remove the solvent under areduced pressure. Resulting residue was applied to a silica gel columnand eluted with 1% methanol in chloroform to obtain 650 mg of the titlecompound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.50-1.67 (2H, m), 1.75-1.94 (2H, m), 2.15-2.30(2H, m), 2.40-2.96 (6H, m), 3.00 (3H, s), 3.39 (1H, m), 3.96 (1H, m),4.47 (2H, s), 6.26 (2H, brd, J=8.5 Hz), 6.61 (2H, brd, J=8.5 Hz),6.90-7.10 (1H, br), 7.16 (1H, dd, J=8.3, 1.9 Hz), 7.41 (1H, d, J=8.3Hz), 7.44 (1H, d, J=1.9 Hz), 7.60 (1H, dd, J=8.0, 7.5 Hz), 8.09 (1H,brd, J=6.1 Hz), 8.14 (1H, brd, J=8.0 Hz), 8.31 (1H, dd, J=7.5, 1.2 Hz),8.47 (1H, d, J=6.1 Hz), 9.28 (1H, brs).

EXAMPLE 91N-{2-[4-(3,4-Dichlorobenzyloxy)piperidine]-1-(p-methoxybenzyl)ethyl)-N-methyl-5-isoquinolincsulfonamide

350 mg of the amorphous compound obtained in Example 90 was dissolved in10 ml of dimethylformamide, and to the solution 82.8 mg of methyl iodidewas added with stirring in an ice bath. The mixture was stirred for 30minutes, and after removing the ice bath further stirred for 2 hours ata room temperature. To the reaction mixture was added 100 ml of ethylacetate, and the mixture was washed three times with 50 ml of water. Thewashing were extracted with 50 ml of ethyl acetate, the ethyl acetatelayer was washed with water. The ethyl acetate layers were combined,washed with saturated sodium chloride aqueous solution, dried overmagnesium sulfate, and evaporated to remove the solvent under a reducedpressure. Resulting residue was applied to a silica gel column andeluted with 1% methanol in chloroform to obtain 297 mg of the titlecompound in a colorless amorphous form.

IR (CHCl₃) cm⁻¹ : 2910, 2835, 1615, 1585, 1322, 1125, 986;

¹ H-NMR (CDCl₃, δ ppm): 1.38-1.60 (2H, m), 1.69-1.85 (2H, m), 2.06-2.22(2H, m), 2.36 (1H, dd, J=13.0, 7.3 Hz), 2.51-2.76 (4H, m), 2.88 (1H, m),2.93 (3H, s), 3.34 (1H, m), 3.73 (3H, s), 4.13 (1H, m), 4.44 (2H, s),6.50 (2H, dm, J=8.8 Hz), 6.83 (2H, dm, J=8.8 Hz), 7.14 (1H, dd, J=8.0,1.9 Hz), 7.40 (1H, d, J=8.0 Hz), 7.43 (1H, d, J=1.9 Hz), 7.56 (1H, dd,J=8.3, 7.3 Hz), 8.08 (1H, brd, J=8.3 Hz), 8.29 (1H, dd, J=7.3, 1.2 Hz),8.55 (1H, d, J=6.3 Hz), 9.23 (1H, brs).

EXAMPLE 92

The same procedures as described in Examples 34 and 35 were sequentiallyrepeated except that1-[2-amino-3-(p-hydroxyphenyl)propyl]-4-phenylpiperidine was used inplace of 1-[2-amino-3-(p-hydroxyphenyl)propyl]-4-phenylpiperazine, toobtainN-{1-[p-(5-isoquinolinesulfonyloxy)benzyl]-2-(4-phenylpiperidino)ethyl}-N-methyl-5-isoquinolinesulfonamidein a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.15-1.75 (4H, m), 1.80-2.10 (2H, m), 2.20-2.50(3H, m), 2.60-2.80 (2H, m), 2.80-3.05 (3H, m), 2.86 (3H, s), 4.13 (1H,d, J=6.85 Hz), 6.62 (2H, d, J=7.99 Hz), 6.91 (2H, d, J=7.99 Hz), 7.12(2H, dd, J=6.85, 1.0 Hz), 7.16-7.40 (3H, m), 7.58 (1H, t, J=7.42 Hz),7.61 (1H, t, J=7.42 Hz), 8.11 (1H, d, J=7.42 Hz), 8.26 (3H, dd, J=6.85,1.0 Hz), 8.36 (1H, dd, J=7.42, 1.0 Hz), 8.56 (1H, d, J=6.28 Hz), 8.59(1H, d, J=6.28 Hz), 8.83 (1H, d, J=6.28 Hz), 9.28 (1H, s), 9.41 (1H, d,J=1.0 Hz).

EXAMPLE 93

The amorphous compound obtained in Example 92 was subjected to alkalinehydrolysis according to the procedure in Example 36, to obtainN-[1-(p-hydroxybenzyl)-2-(4-phenylpiperidino)ethyl]-N-methyl-5-isoquinolinesulfonamidein a colorless amorphous form.

IR (KBr) cm⁻¹ : 1615, 1515, 1325, 1125;

¹ H-NMR (CDCl₃, δ ppm): 1.55-1.95 (5H, m), 2.22 (2H, dt, J=6.28, 1.7Hz), 2.35-2.60 (3H, m), 2.70 (1H, dd, J=12.56, 5.71 Hz), 2.8-3.25 (3H,m), 3.06 (3H, s), 3.98 (1H, m), 6.23 (2H, d, J=8.57 Hz), 6.59 (2H, d,J=8.57 Hz), 7.15-7.40 (5H, m), 7.62 (1H, t, J=7.42 Hz), 8.10 (1H, d,J=6.85 Hz), 8.16 (1H, d, J=7.42 Hz), 8.35 (1H, dd, J=7.42, 1.0 Hz), 8.47(1H, d, J=6.28 Hz), 8.29 (1H, s).

EXAMPLE 94

The same procedures as described in Examples 34 and 35 were sequentiallyrepeated except that1-[2-amino-3-(p-hydroxyphenyl)propyl]-4,4-ethylenedioxypiperidine wasused in place of1-[2-amino-3-(p-hydroxyphenyl)propyl]-4-phenylpiperazine, to obtainN-{2-(4,4-ethylenedioxypiperidino)-1-[p-(5-isoquinolinesulfonyloxy)benzyl]ethyl}-N-methyl-5-isoquinolinesulfonamidein a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.4-1.6 (4H, m), 2.22 (1H, dd, J=12.56, 6.85Hz), 2.25-2.5 (5H, m), 2.6-2.8 (1H, m), 2.8-2.95 (1H, m), 2.84 (3H, s),3.90 (4H, s), 4.11 (1H, q, J=6.85 Hz), 6.61 (2H, d, J=8.57 Hz), 6.89(2H, d, J=8.57 Hz), 7.61 (1H, t, J=7.42 Hz), 7.63 (1H, t, J=7.42 Hz),8.12 (1H, d, J=7.42 Hz), 8.26 (2H, d, J=7.42 Hz), 8.27 (1H, d, J=7.42Hz), 8.35 (1H, d, J=7.42 Hz), 8.57 (1H, d, J=6.28 Hz), 8.58 (1H, d,J=6.28 Hz), 8.84 (1H, d, J=6.28 Hz), 9.29 (1H, s), 9.42 (1H, s).

EXAMPLE 95N-{1-[p-(5-Isocuinolinesulfonyloxy)benzyl]-2-(4-oxopiperidino)ethyl}-N-methyl-5-isoquinolinesulfonamide

2.57 g of the product of Example 94 was dissolved in 50 ml of 3Nhydrochloric acid, and after refluxing for 6 hours and then cooling, thereaction mixture was alkalized with saturated sodium bicarbonate aqueoussolution and extracted twice with 200 ml of chloroform. The extract wasdried over magnesium sulfate and evaporated under a reduced pressure toremove the solvent, and resulting residue was applied to a silica gelcolumn and eluted with chloroform/methanol (50:1) to obtain 2.22 g ofthe title compound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 2.1-2.25 (4H, m), 2.31 (1H, dd, J=13.13, 6.85Hz), 2.4=2.65 (6H, m), 2.65-2.85 (1H, m), 2.79 (3H, s), 4.10 (1H, q,J=6.85 Hz), 6.52 (2H, d, J=7.71 Hz), 6.78 (2H, d, J=7.71 Hz), 7.49 (1H,t, J=7.42 Hz), 7.55 (1H, t, J=7.42 Hz), 8.05 (1H, d, J=7.99 Hz),8.10-8.20 (3H, m), 8.20 (1H, d, J=7.42 Hz), 8.46 (1H, d, J=6.28 Hz),8.48 (1H, d, J=6.28 Hz), 8.76 (1H, d, J=6.28 Hz), 9.20 (1H, s), 9.34(1H, s).

EXAMPLE 96N-{2-4-(N'-Benzyl-N'-methylamino)piperidino]-1-[p-(5-isoquinolinesulfonyloxy)benzyl]ethyl}-N-methyl-5-isoquinolinesulfonamide

1.0 g of the product of Example 95 was dissolved in 15 ml of methanol,to the solution were added 270 mg of benzylmethylamine and 120 mg ofsodium cyanoborohydride at a room temperature with stirring, and thereaction mixture was stirred for 18 hours. After addition of saturatedsodium bicarbonate aqueous solution, the reaction mixture was twiceextracted with 150 ml of chloroform. The extract was dried overmagnesium sulfate and evaporated under a reduced pressure to remove thesolvent, and resulting residue was applied to a silica gel column andeluted with chloroform/methanol (30:1), to obtain 380 mg of the titlecompound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.0-1.45 (2H, m), 1.45-1.65 (1H, m), 1.65-2.0(3H, m), 2.13 (3H, s), 2.15-2.45 (3H, m), 2.5-2.9 (4H, m), 2.84 (3H, s),3.49 (3H, s), 4.07 (1H, q, J=6.85 Hz), 6.61 (2H, d, J=7.99 Hz), 6.89(2H, d, J=7.99 Hz), 7.28 (5H, s), 7.58 (1H, t, J=7.42 Hz), 7.60 (1H, t,J=7.42 Hz), 8.11 (1H, d, J=7.99 Hz), 8.25 (1H, d, J=6.28 Hz), 8.26 (2H,d, J=7.42 Hz), 8.34 (1H, dd, J=7.42, 1.0 Hz), 8.55 (1H, d, J=6.28 Hz),8.57 (1H, d, J=6.28 Hz), 8.83 (1H, d, J=6.28 Hz), 9.26 (1H, s), 9.41(1H, s).

EXAMPLE 97N-{2-4-(N-Benzyl-N-methylamino)piperidino]-1-(p-hydroxybenzyl)ethyl}-N-methyl-5-isocuinolinesulfonamide

380 mg of the amorphous compound obtained in Example 96 was dissolved in2 ml of tetrahydrofuran and 2 ml of methanol, to the solution was added4 ml of 1 N sodium hydroxide aqueous solution, and the mixture wasrefluxed for 3 hours and cooled. The reaction mixture was poured towater, acidified with citric acid and then alkalized with sodiumbicarbonate, washed with a small amount of methanol, and extracted twicewith 100 ml of chloroform. The extract was dried over magnesium sulfateand evaporated to remove the solvent under a reduced pressure, andresulting residue was applied to a silica gel column and eluted withchloroform/methanol (20:1) to obtain 147 mg of the title compound in acolorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.35-1.95 (4H, m), 1.95-2.25 (2H, m), 2.19 (3H,s), 2.3-2.7 (4H, m), 2.75-3.15 (3H, m), 3.01 (3H, s), 3.57 (2H, s), 3.95(1H, m), 6.25 (2H, d, J=8.3 Hz), 6.58 (2H, d, J=8.55 Hz), 7.2-7.4 (5H,m), 7.60 (1H, t, J=7.57 Hz), 8.11 (1H, d, J=5.86 Hz), 8.12 (1H, d,J=8.06 Hz), 8.32 (1H, d, J=7.33 Hz), 8.46 (1H, d, J=6.35 Hz), 9.28 (1H,s).

EXAMPLE 98

The same procedures as described in Examples 96 and 97 were sequentiallyrepeated except that benzylamine was used in place of benzylmethylamine,to obtainN-{2-[4-(N-benzylamino)piperidino]-1-(p-hydroxybenzyl)ethyl}-N-methyl-5-isoquinolinesulfonamidein a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.2-1.6 (2H, m), 1.7-2.0 (2H, m), 2.0-2.3 (2H,m), 2.35-2.7 (4H, m), 2.7-3.5 (3H, m), 3.0 (3H, s), 3.83 (2H, s), 3.95(1H, m), 6.24 (2H, d, J=7.99 Hz), 6.56 (2H, d, J=7.99 Hz), 7.32 (5H, m),7.59 (1H, t, J=7.42 Hz), 8.10 (1H, d, J=6.28 Hz), 8.12 (1H, d, J=7.42Hz), 8.30 (1H, d, J=7.42 Hz), 8.46 (1H, d, J=6.28 Hz), 9.26 (1H, s).

EXAMPLE 99N-{2-(4-hydroxypiperidino)-1-p-(5-isoquinolinesulfonyloxy)benzyl]ethyl)-N-methyl-5-isoquinolinesulfonamide

200 mg of the amorphous compound obtained in Example 95 was dissolved in5 ml of methanol, to the solution was added in portions 35.2 mg ofsodium borohydride at a room temperature with stirring, and the mixturewas stirred for 2 hours and evaporated to remove the solvent. Resultingresidue was applied to a silica gel column and eluted withchloroform/methanol (100:4), to obtain 116 mg of the title compound aspale yellow oil.

IR (KBr) cm⁻¹ : 1620, 1500, 1370, 1320, 1130, 860;

¹ H-NMR (CDCl₃, δ ppm): 1.2-1.4 (2H, m), 1.5-1.8 (4H, m), 1.9-2.1 (2H,m), 2.25 (1H, dd, J=12.6, 7.3 Hz), 2.4 (1H, dd, J=12.7, 7.1 Hz), 2.7(1H, dd, J=13.8, 7.0 Hz), 2.8-2.95 (1H, m), 2.55 (1H, brs), 2.83 (3H,s), 3.55 (1H, m), 4.1 (1H, m), 6.6 (2H, d, J=8.5 Hz), 6.87 (2H, d, J=8.5Hz), 7.6 (1H, t, J=8.3 Hz), 7.63 (1H, t, J=7.8 Hz), 8.12 (1H, d, J=8.3Hz), 8.23 (1H, d, J=5.1 Hz), 8.26 (1H, d, J=5.1 Hz), 8.3 (1H, dd, J=1.2,3.3 Hz), 8.54 (1H, d, J=4.1 Hz), 8.57 (1H, d, J=4.1 Hz), 8.83 (1H, d,J=6.1 Hz), 9.28 (1H, s), 9.4 (1H, s).

EXAMPLE 100N-{2-(4-Hydroxypiperidino)-1-[p-(5-isoquinolinesulfonyloxy)benzylethyl)-N-methyl-5-isoquinolinesulfonamide

150 mg of the oil obtained in Example 99 was dissolved in 3 ml ofmethanol, to the solution was added 1 ml of 10% sodium hydroxide aqueoussolution, and the reaction mixture were refluxed for 2 hours andevaporated to remove the solvent under a reduced pressure, the resultingresidue was acidified with citric acid and then alkalized with a sodiumbicarbonate aqueous solution, and the mixture was extracted three timeswith 20 ml of chloroform. The extract was dried over magnesium sulfateand evaporated to remove the solvent under a reduced pressure, and theresulting residue was subjected to a silica gel preparative thin layerchromatographic and separated b chloroform/methanol (20:1), to obtain 87mg of the title compound in a colorless amorphous form.

IR (KBr) cm⁻¹ : 1610, 1510, 1320, 1150, 1125;

¹ H-NMR (CDCl₃, δ ppm): 1.4-1.7 (2H, m), 1.8-2.0 (2H, m), 2.1-2.4 (4H,m), 2.3-2.6 (1H, m), 2.7 (1H, dd, J=12.7, 4.8 Hz), 2.8 (1H, dd, J=14.6,4.7 Hz), 2.95 (1H, dd, J=12, 2.5 Hz), 2.99 (3H, s), 3.7 (1H, m), 3.9(1H, m), 6.15 (2H, d, J=8.3 Hz), 6.5 (2H, d, J=8.3 Hz), 7.6 (1H, t,J=7.6 Hz), 8.0 (1H, d, J=6.1 Hz), 8.15 (1H, d, J=8.3 Hz), 8.33 (1H, dd,J=7.3, 1.0 Hz), 8.4 (1H, d, J=6.1 Hz), 9.24 (1H, s).

EXAMPLE 101 N-[1-(p-Hydroxybenzyl)-2-(4-hydroxypiperidino)ethyl]-N-methyl-5-isoquinolinesulfonamide

100 mg of the amorphous compound obtained by Example 100 was dissolvedin 5 ml of a mixture of ethyl acetate/methanol (1:1), to the solutionwas added an excess amount of diazomethane in ether, and the reactionmixture was allowed to stand overnight at a room temperature. Thesolvent in the reaction mixture was evaporated off under a reducedpressure, and resulting residue was subjected to a silica gelpreparative thin layer chromatography and separated bychloroform/methanol (20:1) to obtain 80.4 mg of the title compound incolorless amorphous form.

IR (KBr) cm⁻¹ : 1510, 1320, 1240, 1150, 1120, 1030;

¹ H-NMR (CDCl₃, δ ppm): 1.3-1.5 (2H, m), 1.7-2.0 (4H, m), 2.0-2.3 (2H,m), 2.35 (1H, dd, J=13.0, 7.1 Hz), 2.55 (1H, dd, J=10.0, 6.9 Hz), 2.62(1H, dd, J=10.3, 7.3 Hz), 2.89 (1H, dd, J=14.8, 6.3 Hz), 2.6-2 75 (1H,m), 2.93 (3H, s), 3.6 (1H, m), 4.12 (1H, m), 3.73 (3H, s), 6.5 (2H, d,J=8.7 Hz), 6.84 (1H, d, J=8.7 Hz), 7.56 (1H, t, J=8.0 Hz), 8.1 (1H, d,J=8.3 Hz), 8.2 (1H, d, J=6.1 Hz), 8.3 (1H, d, J=7.3 Hz), 8.55 (1H, d,J=6.1 Hz), 9.24 (1H, s).

EXAMPLE 102N-1-(p-Acetoxybenzyl)-2-(4-acetoxypiperidino)ethyl-N-methvl-5-isocuinolinesulfonamide

230 mg of the amorphous compound obtained in Example 100 was dissolvedin 2 ml of pyridine, to the solution was added 1 ml of acetic anhydride,and the reaction mixture was allowed to stand overnight at a roomtemperature. To the mixture was added 20 ml of ice water, and themixture was stirred for one hour and extracted twice with 20 ml of ethylacetate. The extract was washed with saturated sodium chloride aqueoussolution, dried over magnesium sulfate and evaporated to remove thesolvent under a reduced pressure. Resulting residue was applied to asilica gel column and eluted with chloroform/methanol (100:1) to obtain234.3 mg of the title compound in a colorless amorphous form.

IR (KBr) cm⁻¹ : 1760, 1730, 1360, 1320, 1240, 1215, 1200, 1030;

¹ H-NMR (CDCl₃, δ ppm): 1.58 (3H, s), 2.03 (3H, s), 2.30 (3H, s), 2.91(3H, s), 1.4-1.8 (4H, m), 2.2-2.9 (4H, m), 4.2 (1H, m), 4.7 (1H, m),6.77 (2H, d, J=6.6 Hz), 6.8 (2H, d, J=6.6 Hz), 7.5 (1H, t, J=8.0 Hz),8.1 (1H, d, J=8.1 Hz), 8.2 (1H, d, J=7.4 Hz), 8.29 (1H, d, J=6.1 Hz),8.57 (1H, d, J=6.1 Hz), 9.27 (1H, s).

EXAMPLE 103

The same procedure as described in Example 84 was repeated except thatN-{2-(tert-butoxycarbonylamino)-3-[p-(2-methoxyethoxymethoxy)phenyl]propyl)-4-acetoxypiperidinesynthesized in a similar manner was used in place ofN-{2-(tert-butoxycarbonylamino)-3-[p-(2-methoxyethoxymethoxy)phenyl]propyl}-4-(p-methylbenzyloxy)piperidine,to obtainN-{2-[4-acetoxypiperidino]-1-[p-(5-isoquinolinesulfonyloxy)benyl]ethyl}-5-isoquinolinesulfonamidein a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 0.8-1.05 (1H, m), 1.2-1.55 (3H, m), 1.6-2.15(5H, m), 1.99 (3H, s), 2.15-2.33 (1H, m), 2.73 (1H, dd, J=13.13, 6.85Hz), 2.89 (1H, dd, J=13.13, 4.57 Hz), 3.22 (1H, m), 4.51 (1H, m), 5.43(1H, br), 6.70 (2H, d, J=8.57 Hz), 6.91 (1H, d, J=8.57 Hz), 7.66 (1H, t,J=7.42 Hz), 7.68 (1H, d, J=7.42 Hz), 8.20 (1H, d, J=7.42 Hz), 8.30 (2H,d, J=7.42 Hz), 7.39 (1H, dd, J=7.42, 1.0 Hz), 8.42 (1H, d, J=6.28 Hz),8.53 (1H, d, J=6.29 Hz), 8.70 (1H, d, J=6.28 Hz), 8.81 (1H, d, J=6.28Hz), 9.34 (1H, s), 9.43 (1H, s).

EXAMPLE 104N-{2-[4-Hydroxypiperidino-1-p-(5-isoquinolinesulfonyloxy)benzyl]ethyl}-5-isoquinolinesulfonamide

1.5 g of the product obtained in the Example 103 was dissolved in 8 mlof methanol, to the solution was added 8 ml of 1N sodium hydroxideaqueous solution, and the mixture was stirred for two hours, and afteradding water, extracted twice with 100 ml of chloroform. The extract waswashed with a saturated sodium chloride aqueous solution, dried overmagnesium sulfate and evaporated to remove the solvent under a reducedpressure. The Resulting residue was applied to a silica gel column aneluted with chloroform/methanol (30:1), to obtain 800 mg of the titlecompound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 0.6-0.9 (1H, m), 1.05-1.3 (1H, m), 1.3-1.5 (2H,m), 1.5-1.9 (3H, m), 1.9-2.2 (2H, m), 2.2-2.4 (1H, m), 2.72 (1H, dd,J=13.70, 6.85 Hz), 2.89 (1H, dd, J=1.82, 4.57 Hz), 3.19 (1H, m), 3.46(1H, m), 6.72 (2H, d, J=8.57 Hz), 6.72 (2H, d, J=8.57 Hz), 7.66 (1H, t,J=7.42 Hz), 7.69 (1H, t, J=7.42 Hz), 8.21 (1H, d, J=7.99 Hz), 8.29 (2H,d, J=7.42 Hz), 8.41 (1H, d, J=7.99 Hz), 8.44 (1H, d, J=6.28 Hz), 8.53(1H, d, J=6.28 Hz), 8.69 (1H, d, J=6.28 Hz), 8.81 (1H, d, J=6.28 Hz),9.35 (1H, s), 9.42 (1H, s).

EXAMPLE 105N-3,4-Dichlorobenzyl-N-[1-(p-hydroxybenzyl)-2-(4-hydroxypiperidino)ethyl]-5-isoquinolinesulfonamide

400 mg of the amorphous compound obtained in Example 104 was dissolvedin 5 ml of dimethylformamide, to the solution were added 130 mg of3,4-dichlorobenzyl chloride and 28 mg of 60% sodium hydride withstirring under ice cooling, and the mixture was al.owed to warm to aroom temperature and stirred for 18 hours. After adding saturated sodiumchloride aqueous solution, the reaction mixture was extracted twice with100 ml of chloroform, and the extract was washed with saturated sodiumchloride aqueous solution, dried over magnesium sulfate and evaporatedto remove the solvent under a reduced pressure. The resulting residuewas applied to a silica gel column and eluted with chloroform/methanol(30:1), to obtain 228 mg ofN-(3,4-dichlorobenzyl)-N-{2-(4-hydroxypiperidino)-1-[P-(5-isoquinolinesulfonyloxy)benzyl]ethyl}-5-isoquinolinesulfonamide.

228 mg of the above compound was dissolved in 1.5 ml of methanol, to thesolution was added 1 ml of 1N sodium hydroxide aqueous solution, and themixture was refluxed for 3 hours and then cooled, and after dilutionwith water, acidified with citric acid and then alkalized with sodiumbicarbonate, and extracted twice with 100 ml of chloroform. The extractwas dried over magnesium sulfate and evaporated to remove the solvent,and resulting residue was applied to a silica gel column and eluted withchloroform/methanol (20:1) to obtain 162 mg of the title compound in acolorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.2-1.6 (2H, m), 1.6-2.0 (3H, m), 2.0-2.2 (2H,m), 2.4-2.9 (5H, m), 3.5 (1H, m), 4.21 (1H, q, J=6.08 Hz), 4.44 (1H, d,J=16.36 Hz), 4.66 (1H, d, J=16.11 Hz), 6.51 (2H, d, J=8.55 Hz), 6.79(2H, d, J=8.55 Hz), 7.17 (1H, dd, J=8.30, 1.96 Hz), 7.25 (1H, d, J=8.06Hz), 7.33 (1H, d, J=1.96 Hz), 7.57 (1H, t, J=7.57 Hz), 8.12 (1H, d,J=8.3 Hz), 8.25 (1H, d, J=6.10 Hz), 8.33 (1H, dd, J=7.32, 0.98 Hz), 8.50(1 H, d, J=5.86 Hz), 9.21 (1H, s).

EXAMPLE 106N-[1-(p-Hydroxybenzyl)-2-(4-hydroxypiperidino)ethyl]-N-p-methylbenzyl-5-isoquinolinesufonamide

The same procedure as described in Example 105 was repeated except that4-methylbenzyl chloride was used in place of 3,4-dichlorobenzyl chloridewas used to obtain the title compound in colorless amorphous form.

¹ H-NMR (CDCl₃ +CD₃ OD, δ ppm): 1.2-1.55 (2H, m), 1.55-2.15 (5H, m),2.33 (3H, s), 2.33-2.85 (5H, m), 3.5 (1H, m), 3,98 (1H, q, J=6.59 Hz),4.52 (1H, d, J=15.63 Hz), 4.78 (1H, d, J=15.62 Hz), 6.36 (2H, d, J=8.05Hz), 6.66 (2H, d, J=8.06 Hz), 7.08 (2H, d, J=7.56 Hz), 7.29 (2H, d,J=7.57 Hz), 7.60 (1H, t, J=7.57 Hz), 8.12 (1H, d, J=8.06 Hz), 8.28 (1H,d, J=6.10 Hz), 8.39 (1H, d, J=7.32 Hz), 8.48 (1H, d, J=6.35 Hz), 9.20 (1H, s).

EXAMPLE 107N-{2-(4-Hydroxypiperidino)-1-[p-(5-isoquinolinesulfonyloxy)benzyl]ethyl)-N-methyl-5-isoquinolinesulfonamide

The amorphous compound obtained in Example 103 was treated with methyliodide according to the procedure in Example 89 and the intermediateproduct was subjected to alkaline hydrolysis according to the procedurein Example 104, to obtain the same product as in Example 99.

¹ H-NMR (CDCl₃, δ ppm): 1.20-1.42 (2H, m), 1.68 (2H, m), 2.01 (2H, m),2.22 (1H, dd, J=7.3, 13.2 Hz), 2.40 (1H, dd, J=7.3, 13.2 Hz), 2.43-2.60(2H, m), 2,66 (1H, dd, J=6.8, 13.7 Hz), 2.84 (3H, S), 2.85 (1H, dd,J=6.4, 13.7 Hz), 3,58 (1H, m), 4.10 (1H, m), 6.61 (2H, d, J=8.8 Hz),6.88 (2H, d, J=8.8 Hz), 7.59 (1H, t, J=7.8 Hz), 7.63 (1H, t, J=7.8 Hz),8.12 (1H, d, J=8.3 Hz), 8.23-8.35 (4H, m), 8.55 (1H, d, J=6.4 Hz), 8.58(1H, d, J=6.4 Hz), 8.83 (1H, d, J=5.9 Hz), 9.29 (1H, s), 9.42 (1H, s).

REFERENCE EXAMPLE 24 1-(N-Benzyloxycarbonyltyrosyl)-4-phenylpiperazine

12.3 g of N-benzyloxycarbonyltyrosine and 6.6 g of N-phenylpiperazinewere dissolved in 150 ml of methylene chloride, and to the solution wasadded 8.4 g of DCC, and the mixture was stirred at a room temperaturefor 5 hours. Precipitated insoluble matter was filtered off and thefiltrate was concentrated under a reduced pressure, and resultingresidue was applied to a silica gel column and eluted with hexane/ethylacetate (1:1 to 1:2) to obtain 10.5 g of the title compound in acolorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 2.63 (1H, m), 2.88-3.24 (6H, m), 3.48 (1H, m),3.68 (2H, m), 4.88 (1H, m), 5.07 (1H, d, J=12.7 Hz), 5.11 (1H, d, J=12.7Hz), 5.34 (1H, br), 5.67 (1H, d, J=8.8 Hz), 6.71 (2H, d, J=8.3 Hz), 6.84(2H, d, J=8.3 Hz), 6.90 (1H, t, J=7.3 Hz), 7.04 (2H, d, J=8.3 Hz), 7.26(2H, t, J=7.3 Hz), 7.34 (5H, s).

EXAMPLE 108 1-[N,O-Bis(5-isoquinolinesulfonyl)tyrosyl]4-phenylpiperazine

4.59 g of the amorphous compound obtained in Reference Example 24 wasdissolved in 50 ml of methanol, to the solution was added 3 g of 5%palladium on carbon, and the mixture was stirred for 17 hours at a roomtemperature in a hydrogen atmosphere. The resulting insoluble matter wasfiltered off, and the filtrate was concentrated under a reduced pressureto obtain a residue, which was then suspended in 50 ml of chloroform. Tothe suspension were sequentially added 5.7 g of 5-isoquinolinesulfonylchloride.HCl and 10 ml of triethylamine with ice cooling, and thenmixture was stirred for 3 hours at a room temperature. After adding 200ml of water, the mixture was extracted twice with 100 ml of chloroform,the extract was dried over magnesium sulfate and concentrated under areduced pressure. Resulting residue was applied to a silica gel columnand eluted with chloroform/methanol (80:1 to 30:1), to obtain 5.46 g ofthe title compound in a yellow amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 2.50-2.90 (7H, m), 2.92-3.17 (2H, m), 3.24 (1H,m), 4.32 (1H, m), 5.99 (1H, br), 6.65 (2H, d, J=8.8 Hz), 6.80 (2H, d,J=7.8 Hz), 6.89 (2H, d, J=8.8 Hz), 6.94 (1H, t, J=7.3 Hz), 7.29 (2H, dd,J=7.3, 8.3 Hz), 7.51 (1H, t, J=7.8 Hz), 7.59 (1H, dd, J=7.3, 8.3 Hz),8.09-8.31 (5H, m), 8.50 (1H, d, J=6.4 Hz), 8.69 (1H, d, J=5.9 Hz), 8.81(1H, d, J=5.9 Hz), 9.28 (1H, s), 9.39 (1H, s).

EXAMPLE 1091-[N,O-Bis(5-isoquinolinesulfonyl)N-methyltyrosyl]-4-phenylpiperazine

2.27 g of the amorphous compound obtained in Example 108 was dissolvedin 30 ml of dimethylformamide, to the solution were sequentially added160 mg of 60% sodium hydride and 0.3 ml of methyl iodide with icecooling, and the mixture was stirred for 90 minutes with ice cooling.After adding 80 ml of water, the reaction mixture was extracted with 100ml of ethyl acetate, and the extract was washed with 80 ml of saturatedsodium chloride aqueous solution, dried over magnesium sulfate andconcentrated under a reduced pressure. The resulting residue was appliedto a silica gel column and eluted with chloroform/methanol (60:1), toobtain 1.8 g of the title compound in a yellow amorphous form.

IR (KBr) cm⁻¹ : 1668, 1475, 1360, 1130;

¹ H-NMR (CDCl₃, δ ppm): 2.45 (1H, dd, J=4.6, 13.1 Hz), 2.63 (1H, m),2.82-3.07 (4H, m), 3.03 (3H, s), 3.13-3.29 (2H, m), 3.43-3.65 (4H, m),5.11 (1H, dd, J=4.6, 10.3 Hz), 6.76 (2H, d, J=8.6 Hz), 6.85 (2H, d,J=8.0 Hz), 6.88 (1H, t, J=8.6 Hz), 7.29 (2H, dd, J=8.0, 8.6 Hz), 7.49(1H, dd, J=8.3, 7.3 Hz), 7.70 (1H, dd, J=8.3, 7.3 Hz), 8.16 (1H, dd,J=1.0, 7.3 Hz), 8.21 (2H, d, J=8.3 Hz), 8.30 (1H, dd, J=1.0, 7.3 Hz),8.41 (1H, d, J=6.4 Hz), 8.51 (1H, d, J=6.4 Hz), 8.68 (1H, d, J=6.4 Hz),8.80 (1H, d, J=6.4 Hz), 9,36 (1H, s), 9.40 (1H, s).

EXAMPLE 1101-[N-(5-Isoquinolinesulfonyl)-N-methyltyrosyl]-4-phenylpiperazine

1.15 g of the amorphous compound obtained in Example 109 was suspendedin 20 ml of methanol, to the solution was added 2 ml of 2N sodiumhydroxide aqueous solution, and the mixture was refluxed for 90 minutes.After adding 100 ml of water, the reaction mixture was extracted twicewith 50 ml of chloroform, and the extract was dried over magnesiumsulfate and concentrated under a reduced pressure. Resulting residue wasapplied to a silica gel column and eluted with chloroform/methanol (80:1to 50:1), to obtain 820 mg of the title compound in a colorlessamorphous form.

IR (KBr) cm⁻¹ : 1638, 1590, 1440, 1326 1150;

¹ H-NMR (CDCl₃, δ ppm): 2.56 (1H, dd, J=5.4, 12.7 Hz), 2.61 (1H, m),2.90-3.22 (3H, m), 3.15 (3H, s), 3.43 (1H, m), 3.51-3.71 (4H, m), 5.13(1H, dd, J=5.9, 9.8 Hz), 5.53 (1H, br), 6.62 (2H, d, J=8.8 Hz), 6.84(2H, d, J=7.8 Hz), 6.89 (1H, t, J=7.3 Hz), 6.90 (2H, d, J=8.3 Hz), 7.26(2H, t, J=7.8 Hz), 7.70 (1H, dd, J=7.3, 8.3 Hz), 8.21 (1H, d, J=8.3 Hz),8.32 (1H, dd, J=1.0, 7.3 Hz), 8.38 (1H, d, J=5.9 Hz), 8.66 (1H, d, J=5.9Hz), 9.33 (1H, br).

EXAMPLE 111

The product of Example 108 was subjected to alkaline hydrolysisaccording to the procedure described in Example 110 to obtain1-[N-(5-isoquinolinesulfonyl)tyrosyl]-4-phenylpiperazine in a yellowamorphous form.

IR (KBr) cm⁻¹ : 1630, 1590, 1510, 1440, 1325, 1220, 1150, 1128;

¹ H-NMR (CDCl₃ --CD₃ OD, δ ppm): 2.60 (1H, m), 2.72-2.77 (2H, m), 2.88(4H, m), 3.10-3.43 (3H, m), 4.37 (1H, t, J=7.8 Hz), 6.40 (2H, d, J=8.3Hz), 6.72 (2H, d, J=8.3 Hz), 6.83 (2H, d, J=7.8 Hz), 6.91 (1H, t, J=7.3Hz), 7.27 (2H, dd, J=7.8, 8.3 Hz), 7.63 (1H, dd, J=7.3, 8.3 Hz), 8.17(1H, d, J=8.3 Hz), 8.30 (1H, dd, J=1.0, 7.3 Hz), 8.38 (1H, d, J=6.4 Hz),8.60 (1H, d, J=6.4 Hz), 9.24 (1H, s).

REFERENCE EXAMPLE 25 N-Benzyloxycarbonylhomopiperazine

To 230 ml of dimethylformamide were added 25 g of homopiperazine and 5.4g of sodium bicarbonate and then 25 ml of water followed by dropwiseaddition of 10 g of benzyloxycarbonyl chloride with stirring under icecooling, and the mixture was stirred at a room temperature overnight.After evaporating off dimethylformamide under a reduced pressure, thereaction mixture was extracted three times with 100 ml of chloroform,and the extract was dried over magnesium sulfate and evaporated toremove the solvent under a reduced pressure. The resulting residue wasapplied to a silica gel column and eluted with chloroform/methanol(9:1), to obtain 9 g of the title compound as a light yellow liquorliquid.

IR (KBr) cm⁻¹ : 1695, 1420;

¹ H-NMR (CDCl₃, δ ppm): 1.8 (2H, m), 2.8-3.0 (4H, m), 3.4-3.65 (4H, m),5.15 (2H, s), 7.4 (5H, s).

REFERENCE EXAMPLE 261-N-(tert-Butoxycarbonyl)-N-methyl]tyrosyl-4-benzyloxycarbonylhomopiperazine

1.0 g of N-tert-butoxycarbonyl-N-methyltyrosine was dissolved in 70 mlof methylene chloride, and after adding 793 mg ofN-benzyloxycarbonylhomopiperazine and adding at a stroke 837 mg of DCCat a room temperature with stirring, the mixture was stirred at a roomtemperature overnight. The solvent was evaporated off under a reducedpressure, and to the resulting residue was added benzene. Insolublematter was filtered off, and the filtrate was applied to a silica gelcolumn and eluted with hexane/ethyl acetate (6:4 to 6:5) to obtain 1.06g of the title compound as a light yellowish oil.

Acetylated derivative of this compound has the following properties.

IR (KBr) cm⁻¹ : 1760, 1695, 1215, 1200;

¹ H-NMR (CDCl₃, δ ppm): 1.3, 1.4 (Total 9H, each s), 1.85 (1H, m), 2.3(3H, s), 2.82 (3H, brs), 2.7-2.9 (2H, m), 3.0-3.8 (8H, m), 5.15 (2H,brs), 7.0 (2H, d, J=8.3 Hz), 7.35 (5H, brs).

REFERENCE EXAMPLE 271-{3'-(p-Acetoxyphenyl)-2'[N-(tert-butoxycarbonyl)-N-methylamino]propyl}-4-benzyloxycarbonylhomopiperazine

3.56 g of the product obtained in Reference Example 26 was dissolved in60 ml of absolute tetrahydrofuran, to the solution was added 20 ml of1.0M borane in tetrahydrofuran with stirring under ice cooling, and themixture was stirred overnight at a room temperature. The solvent wasevaporated off under a reduced pressure, and resulting residue wasdissolved in 10 ml of pyridine. To the solution was added 5 ml of aceticanhydride, and the mixture was allowed to stand overnight at a roomtemperature. After an addition of ice, the mixture was stirred for 30minutes and extracted twice with 60 ml of chloroform. The extract waswashed with saturated sodium chloride aqueous solution, dried overmagnesium sulfate and evaporated to remove the solvent under a reducedpressure. Resulting residue was applied to a silica gel column andeluted with chloroform/methanol (100:1), to obtain 2.0 g of the titlecompound in a light yellow amorphous form.

IR (KBr) cm⁻¹ : 1760, 1690, 1215, 1200;

¹ H-NMR (CDCl₃, δ ppm): 1.25, 1.27 (Total 9H, each s), 1.6-1.9 (2H, m),2.27 (3H, s), 2.4-2.8 (11H, m), 8.6 Hz), 7.1 (2H, d, J=8.6 Hz), 7.25,7.33 (Total 5H, each s).

EXAMPLE 112N-[1-(p-Acetoxybenzyl)-2-(4-benzyloxycarbonylhomopiperazinyl)ethyl]-N-methyl-5-isoquinolinesulfonamide

1 g of the amorphous compound obtained in Reference Example 27 wasdissolved in 28 ml of methylene chloride, to the solution were added 2ml of 2,6-lutidine, and then 2 ml oftert-butyldimethylsilyltrifluoromethane sulfonate with stirring at aroom temperature, and the reaction mixture was stirred for 16 hours.After an addition of ice, the reaction mixture was extracted twice with70 ml of ethyl acetate, and the extract was washed with saturated sodiumchloride aqueous solution, dried over magnesium sulfate and evaporatedto remove the solvent under a reduced pressure. To resulting residuewere added 20 ml of tetrahydrofuran and 4.28 ml of 1.0Mtetrabutylammonium fluoride in tetrahydrofuran with stirring, and thereaction mixture was stirred at a room temperature for 40 minutes. Afteradding ice, the reaction mixture was extracted twice with 70 ml ofchloroform, and the extract was washed with saturated sodium chlorideaqueous solution, dried over magnesium sulfate and evaporated to removethe solvent under a reduced pressure. Resulting residue was applied to asilica gel column and eluted with chloroform/methanol (95:5 to 90:10),to obtain 723 mg of1-[3'-(p-acetoxyphenyl)-2'-(N-methylamino)propyl]-4-benzyloxycarbonylhomopiperazine.

¹ H-NMR (CDCl₃, δ ppm): 1.8 (2H, m), 2.3 (3H, s), 2.48 (3H, d, J=2.0Hz), 2.35-3.8 (9H, m), 3.4-3.6 (4H, m), 5.1 (2H, s), 7.0 (2H, d, J=8.5Hz), 7.2 (2H, brd, J=8.5 Hz), 7.35 (5H, s). 723 mg of the above compoundwas dissolved in 25 ml of dimethylformamide, and to the mixture wasadded 401 mg of triethylamine and then 564 mg of 5-isoquinolinesulfonylchloride.HCl with stirring under ice cooling, and the mixture wasstirred overnight at a room temperature. After adding water, thereaction mixture was extracted twice with 70 ml of ethyl acetate, andthe extract was washed with saturated sodium chloride aqueous solution,dried over magnesium sulfate and evaporated to remove the solvent undera reduced pressure. Resulting residue was applied to a silica gel columnand eluted with chloroform/methanol (100:1) to obtain 796 mg of thetitle compound in a light yellow amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.7 (2H, m), 2.3 (3H, s), 2.7-2.8 (8H, m), 2.90,2.91 (Total 3H, each s), 3.3-3.55 (4H, m), 4.1 (1H, m), 5.1 (2H, s), 6.7(2H, d, J=8.3 Hz), 6.9 (2H, d, J=8.3 Hz), 7.34, 7.36 (Total 5H, each s),7.53, 7.55 (Total 1H, each t, J=7.6 Hz), 8.1 (1H, d, J=6.1 Hz), 8.18(2H, d, J=6.5 Hz), 8.55 (1H, d, J=6.1 Hz), 9.25 (1H, s).

EXAMPLE 113N-[2-(4-Benzyloxycarbonylhomopiperazinyl)-1-(p-hydroxybenzyl)ethyl-N-methyl-5-isoquinolinesulfonamide

400 mg of the amorphous compound obtained in Example 112 was dissolvedin 10 ml of methanol, to the solution was added 2 ml of 10% sodiumhydroxide and the mixture was stirred for 10 minutes. The reactionmixture was acidified with citric acid aqueous solution and thenalkalized with saturated sodium bicarbonate aqueous solution, andextracted twice with 50 ml of chloroform. The extract was dried overmagnesium sulfate and evaporated to remove the solvent under a reducedpressure. The resulting residue was applied to a silica gel column andeluted with chloroform/methanol (100:2) to obtain 339 mg of the titlecompound in a colorless amorphous form.

IR (KBr) cm⁻¹ : 1700, 1330, 1210, 1150, 1120;

¹ H-NMR (CDCl₃, δ ppm): 1.8 (2H, m), 1.37, 1.38 (Total 1H, each dd,J=10.0, 13.8 Hz), 1.55 (1H, dd, J=13.8, 9.8 Hz), 2.75 (4H, m), 2.7 - 3.0(2H, m), 3.0 (3H, s), 3.5 (4H, m), 3.8 (1H, m), 5.13 (2H, s), 6.17 (2H,d, J=8.0 Hz), 6.50, 6.51 (Total 2H, each d, J=8.0 Hz), 7.49, 7.50 (total1H, each t, J=7.7 Hz), 8.03 (1H, d, J=6.1 Hz) 8.13 (1H, d, J=7.8 Hz),8.23 (1H, d, J=7.1 Hz), 6.43 (1H, d, J=6.1 Hz), 9.24 (1H, s), 7 35 (5H,s).

EXAMPLE 114

220 mg of the amorphous compound obtained in Example 113 was dissolvedin 2 ml of acetic acid, to the solution was added 6 ml of 25% hydrogenbromide in acetic acid, and the mixture was stirred at a roomtemperature for 20 minutes. 40 ml of dry ether was added to the reactionmixture to form a white precipitate, which was then alkalized withsaturated sodium bicarbonate aqueous solution and extracted twice with20. ml of chloroform/isopropanol (5:1). The extract was dried overmagnesium sulfate and evaporated to remove the solvent under a reducedpressure, and resulting residue was applied to a silica gel column andeluted with chloroform/methanol (20:80 to 30:70) to obtain 67 mg ofN-[1-(p-hydroxy)benzyl-2-homopiperazinylethyl]-N-methyl-5-isoquinolinesulfonamide as alight yellow oil.

¹ H-NMR (CDCl₃, δ ppm): 1.75 (2H, m), 2.3-3.0 (12H, m), 2.93 (3H, s),3.96 (1H, m), 6.3 (2H, d, J=8.3 Hz), 6.6 (2H, d, J=8.3 Hz), 7.6 (1H, t,J=8.1 Hz), 8.1 (1H, d, J=5.3 Hz), 8.12 (1H, d, J=8.3 Hz), 8.2 (1H, d,J=7.4 Hz), 8.45 (1H, d, J=6.1 Hz), 9.26 (1H, s).

REFERENCE EXAMPLE 281-Benzyloxycarbonyl-4-(N-tert-butoxycarbonyltyrosyl)homopiperazine

15.29 g of N-tert-butoxycarbonyltyrosine and 12.73 g ofN-benzyloxycarbonylhomopiperazine were dissolved in 280 ml oftetrahydrofuran, to the solution were added 8.09 g of1-hydroxybenzotriazole hydrate and 11.77 g of DCC at a room temperaturewith stirring, and the reaction mixture was stirred for 16 hours. Thereaction mixture was evaporated to remove the solvent under a reducedpressure, to the residue was added benzene, and insoluble matter wasfiltered by suction and washed with benzene. The benzene layers werecombined and evaporated off under a reduced pressure. The resultingresidue was applied to a silica gel column and eluted withchloroform/methanol (100:1), to obtain 26.42 g of the title compound incolorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.41 (9H, s), 1.5.-2.0 (2H, m), 2.75-3.05 (2H,m), 3.05-3.7 (8H, m), 4.67 (1H, m), 5.10, 5.12 (Total 2H, each s), 5.25(1H, m), 6.0 (1H, br), 6.68, 6.72 (Tot=1 2H, each d, J =8.57 Hz), 7.02,7.03 (Total 2H, each d, J=8.57 Hz), 7.32, 7.34 (Total 5H, each s).

EXAMPLE 115 N-(2-(4-Benzyloxycarbonyl)homopiperazinyl-1-p-(5-isoquinolinesulfonyloxy) benzyl]ethyl)-5-isoquinolinesulfonamide

3.0 g of the amorphous compound obtained in Reference Example 28 wasdissolved in 20 ml of tetrahydrofuran, to the solution was added 24 mlof 1M borane in tetrahydrofuran, and the mixture was stirred under anitrogen atmosphere at a room temperature for 15 hours. After thereaction was completed, the solvent was evaporated off under a reducedpressure and to the resulting residue was added 3 g of potassiumbicarbonate. The mixture was stirred for 30 minutes at a roomtemperature and extracted twice with 200 ml of chloroform. The extractwas dried over magnesium sulfate and concentrated under a reducedpressure, to obtain1-benzyloxycarbonyl-4-[2-(tert-butoxycarbonyl-amino)-3-(p-hydroxyphenyl)propyl]homopiperazine.

This compound was dissolved in 6 ml of ethyl acetate, to the solutionwas added 30 ml of 4N hydrogen chloride in ethyl acetate, and themixture was stirred at a room temperature for 30 minutes. The reactionmixture was evaporated under a reduced pressure and the resultingresidue was alkalized with a saturated sodium bicarbonate aqueoussolution and extracted twice with 200 ml of chloroform. The extract wasdried over magnesium sulfate and evaporated to remove the solvent undera reduced pressure, to obtain 2.43 g of1-[2-amino-3-(p-hydroxyphenyl)propyl]-4-benzyloxycarbonylhomopiperazine.

This intermediate was dissolved in 65 ml of tetrahydrofuran, to thesolution were added 4.03 g of 5-isoquinolinesulfonyl chloride.HCl and8.9 ml of triethylamine at a room temperature with stirring, and themixture was stirred for 16 hours. After an addition of a saturatedsodium bicarbonate solution, the mixture was extracted twice with 300 mlof chloroform, and the extract was dried over magnesium sulfate andevaporated to remove the solvent under a reduced pressure. Resultingresidue was applied to a silica gel column and eluted withchloroform/methanol (20:1), to obtain 2.26 g of the title compound in acolorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.43 (2H, m), 2.2 (6H, m), 73 (2H, m), 2.9-3.4(5H, m), 5.07 (2H, s), 5.34 (1H, br), 6.62 (2H, d, J=8.57 Hz), 6.84,6.86 (Total 2H, each d, J=8.57 Hz), 7.32, 7.33 (Total 5H, each s), 7.63(1H, t, J=8.28 Hz), 7.67 (1H, m), 8.16 (1H, t, J=8.28 Hz), 7.67 (1H, m),8.16 (1H, t, J=7.42 Hz), 8.22 - 8.45 (4H, m), 8.53 (1H, d, J=6.28 Hz),8.66 (1H, dd, J=6.57, 1.0 Hz), 8.82 (1H, d, J=6.28 Hz), 9.31, 9.34(Total 1H, each s), 9.42 (1H, s).

EXAMPLE 116

1.0 g of the product obtained in Example 115 was dissolved in 5 ml ofmethanol and 5 ml of tetrahydrofuran, to the solution was added 10 ml of1N sodium hydroxide, and the mixture was refluxed for 2 hours and thencooled. The reaction mixture was acidified with citric acid and thenalkalized with sodium bicarbonate, the produced insoluble matter, wasthen dissolved in methanol. The solution was extracted twice with 100 mlof chloroform, and the extract was dried over magnesium sulfate andconcentrated under a reduced pressure. Resulting residue was applied toa silica gel column and eluted with chloroform/methanol (20:1), toobtain 458 mg ofN-{2-(4-benzyloxycarbonyl-homopiperazinyl)-1-(p-hydroxybenzyl)ethyl)-5-isoquinolinesulfonamidein a colorless amorphous form.

huH-NMR (CDCl₃, δ ppm): 1.72 (2H, brs), 2.3-2.9 (8H, m), 3.1-3.7 (5H,m), 5.12 (2H, s), 6.27 (2H, d, J=7.32 Hz), 6.57 (2H, d, J=7.32 Hz), 7.6(1H, br), 7.33 (6H, s), 7.63 (1H, t, J=7.57 Hz), 8.17 (1H, d, J=8.3 Hz),8.33 (2H, d, J=7.08 Hz), 8.52 (1H, brs), 9.28 (1H, brs).

EXAMPLE 117N-{1-[p-(5-Isoquinolinesulfonyloxy)benzyl]-2-homopiperazinylethyl}-5-isoquinolinesulfonamide

To 1.0 g of the product obtained in Example 115, was added 6 ml of 30%hydrogen bromide in acetic acid at a room temperature with stirring, andthe mixture was further stirred for 24 hours. After an addtion of 100 mlof ether the reaction mixture was stirred for 30 minutes to form a salt,which was then colected by filtration, washed with ether and dried in adesiccator. The salt was dissolved in water, and the solution wasalkalized with sodium bicarbonate and extracted twice with 100 ml ofchloroform. The extract was dried with magnesium sulfate and evaporatedto remove the solvent under a reduced pressure, to obtain 830 mg of thetitle compound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.37 (2H, m), 2.1-2.9 (12H, m), 3.22 (1H, m),6.62 (2H, d, J=8.79 Hz), 6.87 (2H, d, J=8.54 Hz), 7.64 (1H, t, J=7.82Hz), 7.66 (1H, t, J=7.82 Hz), 8.18 (1H, d, J=8.31 Hz), 8.23-8.36 (3H,m), 8.40 (1H, d, J=6.35 Hz), 8.53 (1H, d, J=6.1 Hz), 8.67 (1H, d, J=6.11Hz), 8.81 (1H, d, J=6.35 Hz), 9.33 (1H, s), 9.42 (1H, s).

EXAMPLE 118 N-{1-[p-(5-Isoquinolinesulfonyloxy)benzyl-2-[4-(3-phenylpropionyl)homopiperazinyl]ethyl}-5-isoquinolinesulfonamide

420 mg of the amorphous compound obtained in Example 117 was dissolvedin 6 ml of methylene chloride, to the solution were added 125 mg of3-phenylpropionyl chloride and 100 mg of triethylamine at a roomtemperature with stirring, and the mixture was stirred for 17 hours. Thereaction mixture was alkalized with a saturated sodium bicarbonateaqueous solution and extracted twice with 50 ml of chloroform. Theextract was dried over magnesium sulfate and evaporated to remove thesolvent. Resulting residue was applied to a silica gel column and elutedwith chloroform/methanol (30:1) to obtain 400 mg of the title compoundin colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.46 (2H, m), 1.9-2.4 (6H, m), 2.4-2.6 (2H, m),2.6-2.82 (2H, m), 2.82-2.98 (2H, m), 2.98-3.12 (1H, m), 3.12-3.33 (3H,m), 3.4 (1H, t, J=6.28 Hz), 6.61, 6.63 (Total 2H, each d, J=8.57 Hz),6.82, 6.85 (Total 2H, each d, J =8.57 Hz), 7.1-7.35 (5H, m), 7.64 (1H,t, J=8.28 Hz), 7.66 (1H, t, J=8.28 Hz), 8.1-8.45 (5H, m), 8.52 (1H, d,J=6.28 Hz), 8.67 (1H, dd, J=6.28, 1.0 Hz), 8.82 (1H, d, J=6.28 Hz),9.33, 9.34 (Total 1H, each s), 9.42 (1 H, s).

EXAMPLE 119N-{1-(p-Hydroxybenzyl)-2-[4-(3-phenylpropionyl)homopiperazinyl]ethyl)-5-isoquinolinesulfonylamide

400 mg of the amorphous compound obtained in Example 118 was dissolvedin 2 ml of methanol and 2 ml of tetrahydrofuran, to the solution wasadded 4 ml of 1N sodium hydroxide, and the mixture was refluxed for 3hours and then cooled. The reaction mixture was acidified with citricacid and then alkalized with sodium bicarbonate to form an insolublematter, which was then dissolved in a small amount of methanol andextracted twice with 50 ml of chloroform. The extract was dried overmagnesium sulfate and evaporated to remove the solvent under a reducedpressure. Resulting residue was applied to a silica gel column andeluted with chloroform/methanol (30:1), to obtain 230 mg of the titlecompound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.64 (2H, m), 2.3-2.85 (10H, m), 2.96 (2H, t,J=8.3 Hz), 3.15-3.6 (5H, m), 6.31, 6.35 (Total 2H, each d, J=8.30 Hz),6.57, 6.61 (Total 2H, each d, J=8.30 Hz), 7.1-7.4 (5H, m), 7.65 (1H, t,J=8.06 Hz), 8.19 (1H, d, J=8.23 Hz), 8.25-8.4 (2H, m), 8.55 (1H, d,J=6.28 Hz), 9.32 (1H, s).

REFERENCE EXAMPLE 291-Benzyloxycarbonyl-4-(N-tert-butoxycarbonyl-o-methyl)tyrosylhomopiperazine

5.0 g of the amorphous compound obtained in Reference Example 28 wasdissolved in 25 ml of tetrahydrofuran and 25 ml of dimethylformamide, tothe solution was added 0.41 g of 60% sodium hydride with stirring underice cooling, and then the mixture was allowed to warm to a roomtemperature and stirred for 30 minutes. After adding 1.43 g of methyliodide, the reaction mixture was stirred for 16 hours, and after anaddition of a saturated sodium chloride aqueous solution, extractedtwice with 300 ml of chloroform. The extract was dried over magnesiumsulfate and evaporated to remove the solvent under a reduced pressure.Resulting residue was applied to a silica gel column and eluted withchloroform/methanol (100:1), to obtain 3.76 g of the title compound in acolorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.41 (9H, s), 1.65-2.0 (2H, m), 2.8-3.05 (2H,m), 3.05-3.65 (8H, m), 3.77 (3H, s), 5.68 (1H, m), 5.10 (2H, s), 5.23(1H, m), 6.79 (2H, d, J=8.3 Hz), 7.11 (2H, d, J=8.54 Hz), 7.33 (5H, s).

REFERENCE EXAMPLE 30 1-(N-tert-Butoxycarbonyl-o-methyl)tyrosyl-4-phenyl-acetylhomopiperazine

1.02 g of the amorphous compound obtained in Reference Example 29 wasdissolved in 25 ml of methanol, to the solution was added 250 mg of 5%palladium on carbon with ice cooling, and after warming the mixture to aroom temperature, the catalytic reduction was carried out for 6 hours.The catalyst was filtered off and washed with methanol, and the methanolsolution was evaporated to obtain 800 mg of(N-tert-butoxycarbonyl-o-methyl)tyrosylhomopiperazine.

400 mg of the compound was dissolved in 6 ml of methylene chloride, tothe solution were added 195 mg of phenylacety- chloride and 190 mg oftriethylamine, and the mixture was stirred at a room temperature for 24hours. The reaction mixture was alkalized with a saturated sodiumbicarbonate aqueous solution and extracted twice with 100 ml ofchloroform, and the extract was dried over magnesium sulfate andevaporated to remove the solvent under a reduced pressure. Resultingresidue was applied to a silica gel column and eluted withchloroform/methanol (50:1), to obtain 433 mg of the title compound in acolorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.41 (9H, s), 1.6-2.0 (2H, m), 2.7-3.75 (12H,m), 3.77, 3.78 (Total 3H, each s), 4.65 (1H, m), 5.13, 5.24 (Total 1H,each d, J=9.14 Hz), 6.78, 6.79 (Total 2H, each d, J=9.71 Hz), 7.08, 7.11(Total 2H, each d, J=9.71 Hz), 7.28 (5H, m).

EXAMPLE 1201-[N-(5-Isoquinolinesulfonyl)-o-methyltyrosyl-4-phenylacetylhomopiperazine

433 mg of the amorphous compound obtained in Reference Example 30 wasdissolved in 1 ml of ethyl acetate, to the solution was added 4 ml of 4Nhydrogen chloride in ethyl acetate, and after stirring for 30 minutes ata room temperature, the solvent was evaporated off under a reducedpressure. To resulting residue was added a saturated sodium bicarbonateaqueous solution, and the solution was twice extracted with ml ofchloroform. The extract was dried over magnesium sulfate andconcentrated under a reduced pressure. To resulting residue were added 6ml of tetrahydrofuran, as well as 275 mg of 5-isoquinoline-sulfonylchloride.HCl and 1.2 ml of triethylamine at a room temperature withstirring, and the mixture was further stirred for 18 hours. The reactionmixture was alkalized with a saturated sodium bicarbonate aqueoussolution and extracted twice with 50 ml of chloroform, and the extractwas dried over magnesium sulfate and evaporated to remove the solventunder a reduced pressure. Resulting residue was applied to a silica gelcolumn and eluted with chloroform/methanol (30:1), to obtain 439 mg ofthe title compound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.5-1.9 (2H, m), 2.4-2.9 (3H, m), 2.9-4.0 (9H,m), 3.67, 3.68, 3.70 (Total 3H, each s), 4.18 (1H, m), 6.18 (1H, m),6.25 - 6.5 (2H, m), 6.7 (2H, m), 7.28 (5H, m), 7.54, 7.56 (Total 1H,each t, J=7.81 Hz), 8.09 (1H, t, J=7.81 Hz), 8.15-8.3 (2H, m), 8.63 (1H,m), 9.22, 9.26 (Total 1H, each s).

EXAMPLE 1211[-N,O-Dimethyl-N-(5-isoquinolinesulfonyl)tyrosyl-4-phenylacetylhomopiperazine

439 mg of the amorphous compound obtained in Example 120 was dissolvedin 2.5 ml of tetrahydrofuran and 2.5 ml of dimethylformamide, to thesolution was added 30 mg of 60% sodium hydride with ice cooling, andthen the mixture was warmed to a room temperature and stirred for 30minutes. After an addition of 110 mg of methyl iodide, the reactionmixture was further stirred for 16 hours. After an addition of asaturated sodium chloride aqueous solution, the reaction mixture wasextracted twice with 50 ml of chloroform, and the extract was dried overmagnesium sulfate and evaporated to remove the solvent under a reducedpressure. Resulting residue was applied to a silica gel column andeluted with chloroform/methanol (30:1), to obtain 348 mg of the titlecompound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.5-2.0 (2H, m), 2.2-4.0 (12H, m}, 3.03, 3.07,3.08, 3.19 (Total 3H, each s), 3.71, 3.73, 3.75 (Total 3H, each s), 4.9(1H, m), 6.5-6.78 (2H, m), 6.78-7.0 (2H, m), 7.26 (5H, m), 7.68 (1H, m),8.1-8.33 (2H, m), 8.42 (1H, m), 8.66 (1H, m), 9.32 (1H, m).

EXAMPLE 122 1-Benzyloxycarbonyl-4-[N,O-bis(5-isoquinolinesulfonyl)tyrosyl]homopiperazine

6.44 g of the amorphous compound obtained in Reference Example 28 wasdissolved in 6 ml of ethyl acetate, to the solution was added 60 ml of4N hydrogen chloride in ethyl acetate at a room temperature withstirring, and the mixture was stirred for 3 hours. The reaction mixturewas concentrated under a reduced pressure and after an addition ofbenzene, again concentrated under a reduced pressure, to obtain1-benzyloxycarbonyl-4-tyrosylhomopiperazine/hydrochloride in anamorphous form.

To this intermediate were added 130 ml of tetrahydrofuran as well as7.88 g of 5-isoquinolinesulfonyl chloride.HCl and 18 ml oftriethylamine, and the mixture was stirred for 18 hours at a roomtemperature. The reaction mixture was alkalized with a saturated sodiumbicarbonate aqueous solution and extracted twice with 700 ml ofchloroform, and the extract was dried over magnesium sulfate andevaporated to remove the solvent under a reduced pressure. Resultingresidue was applied to a silica gel column and eluted withchloroform/methanol (30:1) to obtain 5.50 g of the title compound in acolorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.65 (2H, m), 2.4-3.8 (10H, m), 4.17 (1H, m),5.1 (2H, m), 6.02 (1H, d, J=9.52 Hz), 6.47, 6.51 (Total 2H, each d,J=8.55 Hz), 6.75 (2H, d, J=8.55 Hz), 7.29, 7.33 (Total 5H, each s),7.58, 7.60 (Total 1H, each t, J=8.06 Hz), 8.1 8.3 (5H, m), 8.52 (1H, d,J=6.11 Hz), 8.64 (1H, d, J=6.10 Hz), 8.84 (1H, d, J=5.37 Hz), 9.29 (1H,s), 9.41 (1H, s).

EXAMPLE 1231-Benzyloxycarbonyl-4-[N-(5-isoquinolinesulfonyl)tyrosyl]homopiperazine

5.50 g of the amorphous compound obtained in Example 122 was dissolvedin 30 ml of methanol and 30 ml of tetrahydrofuran, to the solution wasadded 60 ml of 1N sodium hydroxide, and the mixture was refluxed for 2hours and then cooled. The reaction mixture was acidified with citricacid and then alkalized with sodium bicarbonate, resulting insolublematter was dissolved with a small amount of methanol, and the solutionwas extracted twice with 400 ml of chloroform. The extract was driedover magnesium sulfate and evaporated to remove the solvent under areduced pressure, and resulting residue was applied to a silica gelcolumn and eluted with chloroform/methanol (20:1) to obtain 3.1 g of thetitle compound in a colorless amorphous form.

¹ H-NMR (CDCl₃ +CD₃ OD, δ ppm): 1.82 (2H, m), 2.48 (1H, m), 2.68 (1H,dt, J=6.85, 5.71 Hz), 3.1-3.8 (8H, m), 4.16 (1H, m), 5.12, 5.13 (Total2H, each s), 6.14, 6.17 (Total 2H, each d, J=8.55 Hz), 6.52, 6.53 (Total2H, each d, J=8.55 Hz), 7.33, 7.35 (Total 5H, each s), 7.61 (1H, m),8.16 (1H, d, J=8.06 Hz), 8.2 8.45 (2H, m), 8.53 (1H, d, J=6.11 Hz), 9.21(1H, s).

REFERENCE EXAMPLE 31

N-Benzyloxycarbonyltyrosine and N-tert-butoxycarbonylhomopiperazine weretreated according to the procedure in Reference Example 28 to obtain1-(Nbenzyloxycarbonyl)tyrosyl-4-tertbutoxycarbonylhomopiperazine in acolorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.42, 1.44 (Total 9H, each s), 1.6-2.0 (2H, m),2.7-3.8 (10H, m), 4.75 (1H, m), 5.04 (1H, d, J=11.42 Hz), 5.13 (1H, d,J=11.42 Hz), 5.5 (1H, m), 6.72 (2H, m), 7.02 (2H, m), 7.34 (5H, s).

REFERENCE EXAMPLE 321-(O-Acetyl-N-benzyloxycarbonyl)tyrosyl-4-tert-butoxycarbonylhomopiperazine

690 mg of the amorphous compound obtained in Reference Example 31 wasdissolved in 7 ml of pyridine, and to the solution was added 3.5 ml ofacetic anhydride at a room temperature with stirring, and the mixturewas further stirred for 18 hours. After pouring the reaction mixture tosaturated sodium hydroxide aqueous solution to alkalize, the mixture wasextracted twice with 100 ml of chloroform. The extract was washed with asaturated sodium chloride aqueous solution, dried over magnesiumsulfate, and evaporated to remove the solvent under a reduced pressure.Resulting residue was applied to a silica gel column and eluted withchloroform/methanol (100:1) to obtain 670 mg of the title compound in acolorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.41, 1.43 (Total 9H, each s), 1.5-2.0 (2H, m),2.28 (3H, s), 2.8-3.7 (10H, m), 4.7 (1H, m), 5.05 (1H, d, J=11.4 Hz),5.13 (1H, d, J=11.4 Hz), 5.52 (1H, m), 6.99 (2H, d, J=7.42 Hz), 7.21(2H, d, J=7.42 Hz), 7.34 (5H, s).

REFERENCE EXAMPLE 331-(O-Acetyl-N-benzyloxycarbonyl)tyrosyl-4-(3-phenylpropyl)homopiperazine

670 mg of the amorphous compound obtained in reference Example 32 wasdissolved in 2 ml of ethyl acetate, and to the solution was added 7 mlof 3N hydrogen chloride in ethyl acetate at a room temperature withstirring, and the mixture was further stirred for 30 minutes, alkalizedwith sodium bicarbonate aqueous solution, saturated with sodiumchloride, and extracted twice with 100 ml of ethyl acetate. The extractwas dried over magnesium sulfate and evaporated under a reducedpressure, to obtain 460 mg of1-(0-acetyl-N-benzyloxycarbonyl)tyrosylhomopiperazine.

This compound was dissolved in 6 ml of dimetylformamide, and to thesolution were added 150 mg of potassium carbonate, 160 mg of sodiumiodide and 210 mg of 1-bromo-3-phenylpropane at a room temperature withstirring, and the mixture was stirred for 20 hours. After an addition ofa saturated sodium chloride aqueous solution, the reaction mixture wasextracted twice with 100 ml of chloroform, and the extract was driedover magnesium sulfate and evaporated to remove the solvent under areduced prssure. Resulting residue was applied to a silica gel columnand eluted with chloroform/methanol (100:1) to obtain 430 mg of thetitle compound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.5-2.0 (6H, m), 2.26 (3H, s), 2.3-2.7 (6H, m),2.9-3.8 (6H, m), 4.84 (1H, m), 5.03 (1H, d, J=11.99 Hz), 5.12 (1H, d,J=11.99 Hz), 5.6 (1H, m), 6.97 (2H, dd, J=8.57, 1.0 Hz), 7.1-7.3 (7H,m), 7.33 (5H, s).

REFERENCE EXAMPLE 34 1-(3-Phenylpropyl)-4-tyrosylhomopiperazine

25 430 mg of the amorphous compound obtained in Reference Example 33 wasdissolved in 5 ml of methanol, to the solution was added 120 mg ofpotassium carbonate at a room temperature with stirring, and thereaction mixture was stirred for 70 hours. After an addition of asaturated sodium chloride aqueous solution, the reaction mixture wasacidified with citric acid and extracted twice with 100 ml ofchloroform. The extract was dried over magnesium sulfate and evaporatedto remove the solvent under a reduced pressure. Resulting residue wasapplied to a silica gel column and eluted with chloroform/methanol(100:1) to obtain 395 mg of1-(N-benzyloxycarbonyl)tyrosyl-4-(3-phenylpropyl)homopiperazine.

This compound was dissolved in 15 ml of methanol, and to the solutionwere added 0.05 ml of concentrated hydrochloric acid and 150 mg of 5%palladium on carbon with ice cooling. After warming the reaction mixtureto a room temperature, the catalytic reduction was carried out in ahydrogen atmosphere for 8 hours. The palladium on carbon catalyst wasfiltered by suction, and washed with methanol. The filtrates werecombined and evaporated to remove the solvent under a reduced pressure,and to resulting residue was added saturated sodium chloride aqueoussolution. The mixture was alkalized with a sodium bicarbonate aqueoussolution, precipitated insoluble matter was dissolved by adding a smallamount of methanol, and the mixture was extracted twice with 80 ml ofchloroform. The extract was dried over magnesium sulfate and evaporatedto remove the solvent under a reduced pressure, and resulting residuewas applied to a silica gel column and eluted with chloroform/methanol(20:1), to obtain 180 mg of the title compound in a colorless amorphousform.

¹ H-NMR (CDCl₃, δ ppm): 1.75 (4H, m), 2.3-2.8 (10H, m), 2.92 (1H, m),3.1-3.8 (4H, m), 3.86 (1H, q, J=6.28 Hz), 6.65, 6.66 (Total 2H, each d,J=8.57 Hz), 6.99, 7.00 (Total 2H, each d, J=8.57 Hz), 7.1-7.35 (5H, m).

EXAMPLE 1241-[N-(5-Isoquinolinesulfonyl)tyrosyl]-4-(3-phenylpropyl)homopiperazine

180 mg of the amorphous compound obtained in Reference Example 34 wasdissolved in 4 ml of tetrahydrofuran, and to the solution were added 137mg of 5-isoquinolinesulfonyl chloride.HCl and 0.2 ml of triethylamine ata room temperature with stirring, and the mixture was stirred for 15hours. After an addition of a saturated sodium chloride aqueoussolution, the reaction mixture was alkalized with sodium bicarbonate,and the precipitated insoluble matter was made oily by adding a smallamount of methanol, and the mixture was extracted twice with 50 ml ofchloroform. The extract was dried over magnesium sulfate and evaporatedto remove the solvent under a reduced pressure. Resulting residue wasapplied to a silica gel column and a preparative thin layerchromatographic plate and eluted with chloroform/methanol (10:1), toobtain 130 mg of the title compound in colorless amorphous form.

¹ H-NMR (CDCl₃ +CD₃ OD, δ ppm): 1.76 (4H, m), 2.3-2.8 (10H, m), 3.1-3.7(4H, m), 4.22 (1H, m), 6.17, 6.19 (Total 2H, each d, J=8.57 Hz), 6.53,6.56 (Total 2H, each d, J=8.57 Hz), 7.1-7.4 (5H, m), 7.57, 7.59 (Total1H, each t, J=8.28 Hz), 8.12 (1H, d, J=8.28 Hz), 8.15-8.35 (2H, m), 8.53(1H, dd, J=6.28, 1.0 Hz), 9.18 (1H, s).

EXAMPLE 351-[N-(tert-Butoxycarbonyl)-p-nitrophenylalanyl]-4-(p-methoxyphenyl)piperazine

9.00 g of N-(tert-butoxycarbonyl)-p-nitrophenylalanine was dissolved in120 ml of tetrahydrofuran, 100 ml of methylene chloride and 100 ml ofchloroform, and to the solution were sequentially added 7.68 g ofN-(p-methoxyphenyl) piperazine dihydrochloride and 4.44 g ofN-hydroxybenzotriazole monohydrate as well as 20 ml of triethylamine and6 g of DCC, and the mixture was stirred at a room temperature for 18hours. The reaction mixture was concentrated to one third of theoriginal volume under a reduced pressure, and after adding 200 ml of2.5% potassium carbonate aqueous solution, extracted twice with 200 mlof chloroform. The extract was dried over magnesium sulfate andconcentrated under a reduced pressure to crystallize a product, whichwas washed with methanol to obtain 10.75 g of the title compound ascolorless crystals.

¹ H-NMR (CDCl₃, δ ppm): 1.40 (9H, s), 2.73 (1H, m), 2.87-3.00 (3H, m),3.04 (1H, dd, J=6.3, 13.2 Hz), 3.17 (1H, dd, J=7.3, 13.2 Hz), 3.35 (1H,m), 3.55-3.70 (2H, m), 3.77 (3H, s), 3.84 (1H, m), 4.92 (1H, m), 5.4(1H, d, J=8.8 Hz), 6.83 (4H, s), 7.38 (2H, d, J=8.8 Hz), 8.16 (2H, d,J=8.8 Hz).

REFERENCE EXAMPLE 361-N-(tert-Butoxycarbonyl)-p-aminophenylalanyl]-4-(p-methoxyphenyl)piperazine

10.75 g of the crystals obtained in Reference Example 35 was dissolvedin a mixed solvent of 100 ml of tetrahydrofuran and 20 ml of methanol,and to the solution was added 5 g of 5% palladium on carbon, and themixture was stirred for 2 hours at a room temperature in a hydrogenatmosphere. After filtering off insoluble matter, the filtrate wasconcentrated under a reduced pressure, and resulting residue was appliedto a silica gel column and eluted with chloroform/methanol (200:1 to100:1), to obtain 10.08 g of the title compound in a colorless amorphousform.

¹ H-NMR (CDCl₃, δ ppm): 1.43 (9H, s), 2.42 (1H, m), 2.75-3.00 (4H, m),3.13 (1H, m), 3.43 (1H, m), 3.57 (1H, m), 3.63 - 3.73 (2H, m), 3.76 (3H,s), 4.78 (1H, m), 5.43 (1H, br), 6.59 (2H, d, J=8.3 Hz), 6.82 (4H, s),6.98 (2H, d, J=8.3 Hz).

REFERENCE EXAMPLE 371-[3-(p-Aminophenyl)-2-(tert-butoxycarbonylamino)propyl-4-(p-methoxyphenyl)piperazine

2.54 g of lithium aluminum hydride was suspended in 75 ml oftetrahydrofuran, to the suspension was added a solution of 8.91 g ofaluminum chloride in 75 ml of ether with ice cooling, and also asolution of 10.08 g of the amorphous compound obtained in ReferenceExample 36 in 100 ml of tetrahydrofuran was added dropwise for 20minutes with ice cooling. Under the same condition the mixture wasstirred for one hours, and after terminating the reaction by adding asmall amount of water, 70 ml of 30% potassium carbonate aqueous solutionand 200 ml of chloroform were added to the reaction mixture, which wasthen filtered to remove insoluble matter using silica gel as a filteraid. The insoluble matter was washed with 20% methanol in chloroform,and the filtrates were combined and concentrated under a reducedpressure. 200 ml of saturated sodium bicarbonate aqueous solution wasadded to the residue, the mixture was extracted twice with 100 ml ofchloroform, and the extract was dried over magnesium sulfate andconcentrated under a reduced pressure. Resulting residue was applied toa silica gel column and eluted with chloroform/methanol (100:1) toobtain 7.72 g of the title compound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.43 (9H, s), 2.30 (2H, d, J=6.8 Hz), 2.48-2.68(4H, m), 2.78 (2H, t, J=6.3 Hz), 3.06 (4H, t, J=4.9 Hz), 3.76 (3H, s),3.86 (1H, m), 4.59 (1H, br), 6.62 (2H, d, J=8.3 Hz), 6.82 (2H, d, J=9.3Hz), 6.89 (2H, d, J=9.3 Hz), 6.98 (2H, d, J=8.3 Hz).

REFERENCE EXAMPLE 381-[2-(tert-Butoxycarbonylamino)-3-(p-phthalimidephenyl)propyl]-4-(p-methoxyphenyl)piperazine

7.0 g of the amorphous compound obtained in Reference Example 37 wasdissolved in 70 ml of chloroform, to the solution was added 2.66 g ofphthalic anhydride. The mixture was refluxed for one hour, concentratedunder a reduced pressure, and after an addition of 100 ml of toluene,further refluxed for 2 hours. The solvent was evaporated off under areduced pressure, and resulting residue was applied to a silica gelcolumn and eluted with chloroform/methanol (100:1 to 50:1), to obtain8.91 g of the title compound as colorless crystals.

¹ H-NMR (CDCl₃, δ ppm): 1.45 (9H, s), 2.37 (2H, d, J=6.8 Hz), 2.51-2.71(4H, m), 2.96 (2H, d, J=5.4 Hz), 3.09 (4H, t, J=4.9 Hz), 3.77 (3H, s),4.01 (1H, m), 4.66 (1H, br), 6.83 (2H, d, J=9.3 Hz), 6.90 (2H, d, J=9.3Hz), 7.36 (4H, s), 7.79 (2H, dd, J=3.4, 5.4 Hz), 7.96 (2H, dd, J=3.4,5.4 Hz).

EXAMPLE 125N-{(2-4-(p-Methoxyphenyl)piperazinyl]-1-(p-phthalimidebenzyl)ethyl}-5-isoquinolinesulfonamide

8.91 g of the crystals obtained in Reference Example 38 was dissolved in50 ml of ethyl acetate, to the solution was added 100 ml of 4N hydrogenchloride in ethyl acetate, and the mixture was stirred at a roomtemperature for 1 hour. The reaction mixture was concentrated under areduced pressure, and to the residue was added 200 ml of saturatedsodium bicarbonate aqueous solution, and the mixture was extracted twicewith 100 ml of 20% methanol/chloroform. The extract was dried overmagnesium sulfate and concentrated under a reduced pressure tocrystallize an amino-free compound. The crystals was suspended in 120 mlof tetrahydrofuran, to the suspension were added 5.0 g of5-isoquinolinesulfonyl chloride.HCl and 20 ml of triethylamine with icecooling, and after warming to a room temperature, the mixture wasstirred for 2 hours. After adding 200 ml of water, formed crystals wascollected. The filtrate was extracted twice with 100 ml of chloroform,and the extract was dried over magnesium sulfate and concentrated todryness under a reduced pressure to obtain a residue. The residue withthe crystals was sequentially washed with methanol, ethyl acetate andhexane to obtain 6.49 g of the title compound as colorless crystals.

Melting point: 20420 -211° C. (decomposed);

IR (KBr) cm⁻¹ : 1710, 1510, 1370, 1235, 1150, 1130;

¹ H-NMR (CDCl₃, δ ppm): 2.03-2.33 (6H, m), 2.46-2.59 (2H, m), 2.59-2.72(2H, m), 2.85 (1H, dd, J=7.3, 13.7 Hz), 3.10 (1H, dd, J=4.4, 13.7 Hz),3.41 (1H, m), 3.77 (3H, s), 5.63 (1H, br), 6.73 (2H, d, J=9.3 Hz), 6.83(2H, d, J=9.3 Hz), 7.20 (2H, d, J=8.8 Hz), 7.29 (2H, d, J=8.8 Hz), 7.74(1H, t, J=8.3 Hz), 7.80 (2H, dd, J=3.4, 5.4 Hz), 7.96 (2H, dd, J=3.4,5.4 Hz), 8.24 (1H, d, J=8.3 Hz), 8.48-8.52 (2H, m), 8.72 (1H, d, J=6.4Hz), 9.36 (1H, s).

EXAMPLE 126N-{2-[4-(p-Methoxyphenyl)piperazinyl]-1-(p-phthalimidebenzyl)ethyl}-N-methyl-5-isoquinolinesulfonamide

4.71 g of the crystals obtained in Example 125 was dissolved in 70 ml ofdimethylformamide, to the solution were sequentially added 500 mg of 60%sodium hydride and 1 ml of methyl iodide with ice cooling, and themixture was stirred under the same condition for 3 hours. The reactionwas terminated by adding a small amount of water, and after adding 200ml of saturated ammonium chloride aqueous solution, the mixture wasextracted twice with 100 ml of chloroform. The extract was dried overmagnesium sulfate and concentrated under a reduced pressure. Toresulting residue were added 50 ml of acetic anhydride and 1.2 g ofsodium acetate, and the mixture was stirred for one hour at 80° C. andthen concentrated to dryness under a reduced pressure, and resultingresidue was dissolved in 200 ml of ethyl acetate. The solution wassequentially washed with 100 ml of saturated sodium bicarbonate aqueoussolution and 100 ml of saturated sodium chloride aqueous solution, driedover magnesium sulfate, and concentrated under a reduced pressure.Resulting residue was applied to a silica gel column and eluted withchloroform/methanol (100:1) to obtain 4.84 g of the title compound ascolorless crystals.

Melting point: 170°-172° C.;

IR (KBr) cm⁻¹ : 1710, 1610, 1510, 1375, 1300, 1235, 1145, 1125;

¹ H-NMR (CDCl₃, δ ppm): 2.48 (1H, dd, J=7.3, 13.2 Hz), 2.50-2.63 (4H,m), 2.66 (1H, dd, J=7.3, 13.2 Hz), 2.82 (1H, dd, J=6.8, 14.2 Hz),2.86-2.96 (4H, m), 2.97 (3H, s), 3.02 (1H, dd, J=6.8, 14.2 Hz), 3.77(3H, s), 4.32 (1H, m), 6.84 (4H, s), 7.15 (2H, d, J=8.8, Hz), 7.22 (2H,d, J=8.8 Hz), 7.61 (1H, t, J=7.3 Hz), 7.81 (2H, dd, J=2.9, 5.4 Hz), 7.97(2H, dd, J=2.9, 5.4 Hz), 8.13 (1H, d, J=8.3 Hz), 8.31 (2H, d, J=6.4 Hz),8.60 (1H, d, J= 6.3 Hz), 9.23 (1H, s).

EXAMPLE 127

1.5 g of the crystals obtained in Example 125 was suspended in 30 ml ofethanol, to the suspension was added 3 ml of hydrozine hydrate, and themixture was refluxed for one hour. After adding 10% sodium hydroxideaqueous solution, the reaction mixture was extracted twice with 30 ml ofchloroform. The extract was dried over magnesium sulfate andconcentrated under reduced pressure to form crystals, which was washedwith a mixed solvent of ethyl acetate and methanol, to obtain 1.14 g ofN-{1-(p-aminovenzyl)-2-[4-(p-methoxyphenyl)-piperazinyl]ethyl}-5-isoquinolinesulfonamideas light yellow crystals.

Melting point: 210°-211° C.;

IR (KBr) cm⁻¹ : 1615, 1510, 1330, 1245, 1225, 1150, 1130, 1025;

¹ H-NMR (CDCl₃, δ ppm): 2.12-2.34 (6H, m), 2.53-2.72 (5H, m), 2.85 (1H,dd, J =4.9, 14.2 Hz), 3.31 (1H, m), 3.52 (2H, br], 3.77 (3H, s), 5.48(1H, br), 6.43 (2H, d, J=8.3 Hz), 6.75 (2H, d, J=9.3 Hz), 6.77 (2H, d,J=8.3 Hz), 6.83 (2H, d, J=9.3 Hz), 7.70 (1H, t, J=7.8 Hz), 8.20 (1H, d,J=8.3 Hz), 8.44 (1H, d, J=6.4 Hz), 8.47 (1H, dd, J=1.0, 7.3 Hz), 8.68(1H, d, J=6.4 Hz), 9.35 (1H, s).

EXAMPLE 128

4.64 g of the crystals obtained in Example 126 was suspended in 80 ml ofethanol, to the suspension 8 ml of hydrazine hydrate was added, and themixture was refluxed for 90 minutes. After adding 100 ml of 10% sodiumhydroxide, the reaction mixture was extracted twice with 80 ml ofchloroform, and the extract was dried over magnesium sulfate andconcentrated under a reduced pressure. Resulting residue was applied toa silica gel column and eluted with chloroform/methanol (100 1 to 50:1),to obtain 3.29 g ofN-{1-(p-aminobenzyl)-2-[4-(p-methoxyphenyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamide in a yellow amorphous form.

IR (KBr) cm⁻¹ : 1620, 1510, 1315, 1235, 1150, 1125;

¹ H-NMR (CDCl₃, δ ppm): 2.43 (1H, dd, J=6.8, 13.2 Hz), 2.53-2.66 (6H,m), 2.85 (1H, dd, J=6.4, 14.2 Hz), 2.87-2.94 (4H, m), 2.92 (3H, s), 3.50(2H, br), 3.77 (3H, s), 4.20 (1H, m), 6.34 (2H, d, J=8.3 Hz), 6.75 (2H,d, J=8.3 Hz), 6.84 (4H, s), 6.56 (1H, t, J=7.3 Hz), 8.09 (1H, d, J=8.3Hz), 8.24 (1H, d, J=6.3 Hz), 8.31 (1H, dd, J=1.0, 7.3 Hz), 8.56 (1H, d,J=5.9 Hz], 9.25 (1H, d, J=1.0 Hz).

EXAMPLE 129

500 mg of the amorphous compound obtained in Example 128 was dissolvedin 5 ml of pyridine, to the solution was added 305 mg of5-isoquinolinesulfonyl chloride.HCl under ice cooling, and the mixturewas stirred under the same condition for 20 minutes and then at a roomtemperature for one hour. After adding 30 ml of saturated sodiumbicarbonate aqueous solution, the reaction mixture was extracted twicewith 20 ml of chloroform, and the extract was dried over magnesiumsulfate and concentrated under a reduced pressure. Resulting residue wasapplied to a silica gel column and eluted with chloroform/methanol(50:1), to obtain 665 mg ofN-{1-[p-(5-isoquinolinesulfonylaminobenzyl)]-2-[4-(p-methoxyphenyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamide in a yellow amorphous form.

IR (KBr) cm⁻¹ : 1615, 1510, 1325, 1225, 1150, 1130;

¹ H-NMR (CDCl₃, δ ppm): 2.34 (1H, dd, J=7.3, 12.7 Hz), 2.45-2.61 (6H,m), 2.79-2.94 (5H, m), 2.90 (3H, s), 3.77 (2H, s), 4.04 (1H, m), 6.55(2H, d, J=8.3 Hz), 6.70 (2H, d, J=8.3 Hz), 6.83 (4H, s), 7.57 (2H, t,J=7.8 Hz), 8.08-8.15 (3H, m), 8.28-8.35 (2H, m), 8.40 (1H, d, J=6.4 Hz),8.50 (1H, d, J=5.3 Hz), 8.64 (1H, d, J=6.4 Hz), 9.29 (1H, s), 9.31 (1H,d, J=1.0 Hz).

EXAMPLE 130

200 mg of the crystals obtained in Example 127 was dissolved in 3 ml ofpyridine, to the solution was added 130 mg of 5-isoquinolinesulfonylchloride.1/2 sulfate with ice cooling, and the mixture was stirred withice cooling for 20 minutes and then at a room temperature for one hour,and after adding 30 ml of saturated sodium bicarbonate aqueous solution,extracted twice with 20 ml of chloroform. The extract was dried overmagnesium sulfate and concentrated under a reduced pressure, andresulting residue was applied to a silica gel column and eluted withchloroform/methanol (50:1 to 25:1), to obtain 270 mg ofN-(1-[p-(5-isoquinolinesulfonylaminobenzyl)]-2-[4-(p-methoxyphenyl)piperazinyl]ethyl}-5-isoquinolinesulfonamidein a yellow amorphous form.

IR (KBr) cm⁻¹ : 1615, 1505, 1330, 1230, 1150, 1125;

¹ H-NMR (CDCl₃, δ ppm): 2.16-2.33 (6H, m), 2.49-2.81 (6H, m), 3.28 (1H,m), 3.76 (3H, s}, 6.69 (2H, d, J=8.3 Hz), 6.73 (2H, d, J=9.3 Hz), 6.79(2H, d, J=8.3 Hz), 6.82 (2H, d, J=9.8 Hz), 7.61 (1H, t, J=7.8 Hz), 7.67(1H, t, J=7.8 Hz), 8.16 (1H, d, J=8.3 Hz), 8.19 (1H, d, J=8.3 Hz),8.34-8.48 (4H, m), 8.62 (2H, d, J=6.4 Hz), 9.33 (1H, s), 9.35 (1H., s).

EXAMPLE 131N-[[1-(p-[N-5-Isoquinolinesulfonyl)-N-(methylamino)benzyl]}-2-[4-(p-methoxyphenylpiperazinyl]ethyl]]-N-methyl-5-isoquinolinesulfonamide

503 mg of the amorphous compound obtained in Example 129 was dissolvedin 8 ml of dimethylformamide, to the solution were added 50 mg of 60%sodium hydride and 0.1 ml of methyl iodide with ice cooling, and themixture was stirred for one hours with ice cooling. After adding 30 mlof saturated sodium chloride aqueous solution, the reaction mixture wasextracted with 30 ml of ethyl acetate, and the extract was washed with asaturated sodium chloride aqueous solution, dried over magnesium sulfateand concentrated under a reduced pressure. Resulting residue was appliedto a silica gel column and eluted with chloroform/methanol (100:1), toobtain 488 mg of the title compound in a yellow amorphous form.

IR (KBr) cm⁻¹ : 1610, 1505, 1340, 1320, 1235, 1145, 1125,;

¹ H-NMR (CDCl₃, δ ppm): 2.32 (1H, dd, J=6.4, 13.2 Hz), 2.41-2.56 (5H,m), 2.73-2.98 (6H, m), 2.88 (3H, s), 3.23 (3H, s), 3.77 (3H, s), 4.31(1H, m), 6.82 (4H, s), 6.89 (2H, d, J=8.3 Hz), 7.01 (2H, d, J=8.3 Hz),7.63 (1H, t, J=7.8 Hz), 7.64 (1H, t, J=7.8 Hz), 8.02 (1H, d, J=5.9 Hz),8.13 (1H, d, J=8.3 Hz), 8.19 (1H, d, J=8.3 Hz), 8.23 (1H, d, J=7.3 Hz),8.34 (1H, d, J=6.3 Hz), 8.40-8.47 (2H, m), 8.60 (1H, d, J=5.9 Hz), 9.28(1H, s), 9.29 (1H, s).

EXAMPLE 132N-{1-[p-(4-Picolyloxy)benzyl]-2-4-(2-pyrimidyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamide

100 mg of the amorphous compound obtained in Example 42 was dissolved in10 ml of a mixture of dried tetrahydrofuran/dried dimethylformamide(1:1), to the solution were added 34.8 mg of 4-picolyl chloridehydrochloride and then 24 mg of triethylamine, and the mixture wasstirred at a room temperature for 30 minutes. After adding 10 mg of 60%sodium hydride, the mixture was stirred overnight at a room temperature,and after adding 20 g of water, extracted twice with 20 ml ofchloroform. The extract was washed with a saturated sodium chlorideaqueous solution, dried over magnesium sulfate, and evaporated to removethe solvent under a reduced pressure. The resulting residue was appliedto a silica gel column and extracted with chloroform/methanol (100:1) toobtain 73 mg of the title compound in colorless amorphous form.

NMR (CDCl₃) δ ppm: 2.45 (4H, complex), 2.5-2.75 (2H, complex), 2.95 (3H,s), 3.65 (4H, complex), 4.22 (1H, complex), 5.0 (2H, s), 6.49 (1H, t,J=4.26 Hz), 6.6 (2H, d, J=8.0 Hz), 6.9 (2H, d, J=8.0 Hz), 7.4 (2H, brd),7.6 (1H, t, J=8.3 Hz), 8.11 (1H, d, J=8.3 Hz), 8.23 (1H, d, J=6.64 Hz),8.3 (2H, d, J=4.26 Hz), 8.37 (1H, dd, J=1.0, 6.6 Hz), 8.57 (1H, d, J=6.6Hz), 8.65 (2H, brd), 9.25 (1H, d, J=1.0 Hz).

EXAMPLE 133N-{1-[p-(2-Picolyloxy)benzyl]-2-4-(2-pyrimidyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamide

The same procedure as described in Example 132 was repeated except thatthe same amount of 2-picolyl chloride hydrochloride was used in place of4-picolyl chloride hydrochloride, to obtain 74.4 mg of the titlecompound in colorless amorphous form.

NMR (CDCl₃) δ ppm: 2.45 (4H, complex), 2.5-2.9 (2H, complex), 2.98 (3H,s), 3.75 (4H, complex), 4.2 (1H, complex), 5.13 (2H, s), 6.46 (1H, t,J=4.8 Hz], 6.65 (2H, d, J=8.0 Hz), 6.9 (2H, d, J=8.0 Hz), 7.15 (1H,complex), 7.58 (2H, t, J=6.9 Hz), 7.75 (1H, complex), 8.1 (1H, d, J=8.0Hz), 8.2 - 8.35 (2H, complex), 8.3 (1H, d, J=4.8 Hz), 8.58 (1H, d, J=6.6 Hz), 8.6 (1H, brs), 9.25 (1H, s).

EXAMPLE 134N-{1-p-(4-Picolyloxy)benzyl]-2-[4-(2-pyridyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamide

The same procedure as described in Example 132 was repeated except thatthe product of Example 46 was used in place of the amorphous compoundobtained in Example 42, to obtain the title compound in a colorlessamorphous form in a yield of 53.5%.

NMR (CDCl₃) δ ppm: 2.5 (4H, complex), 2.5-2.75 (2H, complex), 2.95 (3H,s), 3.38 (4H, complex), 4.22 (1H, complex), 5.0 (2H, s), 6.58 (2H, d,J=8.6 Hz), 6.6 (2H, t, J=5.7 Hz), 6.9 (2H, d, J=8.6 Hz), 7.35-7.5 (4H,complex), 7.58 (1H, t, J=7.8 Hz), 8.07 (1H, d, J=8.1 Hz), 8.17 (1H,brd), 8.23 (1H, d, J=6.1 Hz), 8.35 (1H, dd, J=1.0, 7.4 Hz), 8.57 (1H, d,J=6.1 Hz), 8.63 (1H, brd), 8.63 (1H, d, J=5.8 Hz), 9.2 (1H, d, J=1.0Hz).

EXAMPLE 135 N-{1-(p-(2-Picolyloxy)benzyl]-2-[4-(2-pyridyl)piperazinyl]ethyl}-N-methyl-5-isoquinolinesulfonamide

The same procedure as described in Example 133 was repeated except thatthe product of Example 46 was used in place of the amorphous compoundobtained in Example 42, to obtain the title compound in a colorlessamorphous for in a yield of 59.5%.

NMR (CDCl₃) δ ppm: 2.5 (4H, complex), 2.5-2.9 (2H, complex), 2.95 (3H,s), 3.38 (4H, complex), 4.22 (1H, complex), 5.12 (2H, s), 6.55 - 6.65(2H, complex), 6.54 (2H, d, J=8.6 Hz), 6.9 (2H, d, J=8.6 Hz), 7.2-7.25(1H, complex), 7.4-7.7 (4H, complex), 7.65-7.8 (1H, complex), 8.1 (1H,d, J=7.7 Hz), 8.2 (1H, brd), 8.27 (1H, d, J=6.6 Hz), 8.3 (1H, d, J=6.6Hz), 8.57 (1H, d, J=6.3 Hz), 8.6 (1H, brs), 9.73 (1H, s).

EXAMPLE 136N-(2-Aminoethyl)-N-2-(4-benzyloxycarbonylpiperazinyl)-1-(p-methoxybenzyl)ethyl]-5-isoquinolinesulfonamide

1.0 g of the product obtained in Example 73 was dissolved in 5 ml oftetrahydrofuran, to the solution were added 685 mg of triphenylphosphineand 340 mg of N-tert-butoxycarbonylethanolamine, and then added dropwisea solution of 530 mg of diisopropyl azodicarboxylate in 3 ml oftetrahydrofuran with stirring in a ice bath. After removing from the icebath, the mixture was stirred at a room temperature for 3 hours andpoured to water, and the mixture was alkalized with sodium bicarbonateand extracted twice with 150 ml of chloroform. The extract was driedover magnesium sulfate and the solvent was evaporated off under areduced pressure. Resulting oil was dissolved in 2 ml of ethyl acetate,to the solution was added 30 ml of 4N hydrochloric acid in ethylacetate, and the mixture was stirred at a room temperature for 30minutes. After adding 100 ml of 1N hydrochloric acid, the reactionmixture was washed twice with ethyl acetate, and the aqueous layer wasalkalized with sodium Obicarbonate and extracted twice with 150 ml ofchloroform. The extract was dried over magnesium sulfate and evaporatedto remove the solvent under a reduced pressure, and resulting oil wasapplied to a silica gel column and eluted with chloroform/methanol(100:1 to 50:1) to obtain 400 mg of the title compound in colorlessamorphous form.

IR (KBr) cm⁻¹ : 1701, 1514, 1325, 1248, 1135, 763, 601;

NMR (CDCl₃) δ ppm: 1.99 (2H, brs), 2.15-2.40 (5H, m), 2.55-2.80 (3H, m),2.90-3.10 (2H, m), 3.20-3.70 (6H, m), 3.73 (3H, s), 4.98 (1H, m), 5.10(2H, s), 6.54 (2H, d, J=8.55 Hz), 6.77 (2H, J=8.55 Hz), 7.33 (5H, s),7.62 (1H, dd, J=8.06, 7.57 Hz), 8.14 (1H, d, J=8.06 Hz), 8.34 (1H, d,J=6.10 Hz), 8.39 (1H, d, J=7.57 Hz), 8.63 (1H, d, J=6.10 Hz), 9.28 (1H,s).

EXAMPLE 137N-[2-(4-Benzyloxycarbonylpiperazinyl-1-p-methoxybenzyl)ethyl]-N-(2-dimethylaminoethyl)-5-isoquinolinesulfonamide

6.08 g of the product obtained in Example 73 was dissolved in 30 ml oftetrahydrofuran, to the solution were added 5.0 g of triphenylphosphineand 1.42 g of N,N-dimethylethanolamine, and then added dropwise asolution of 3.21 g of diisopropyl azodicarboxylate in 10 ml oftetrahydrofuran with stirring in ice bath. After removing from the icebath, the reaction mixture was stirred at a room temperature for 3hours, diluted with ethyl acetate, and extracted with 100 ml of 1Nhydrochloric acid. The extract was alkalized with sodium bicarbonate andextracted twice with 100 ml of chlorform, and the extract was dried overmagnesium sulfate and evaporated to remove the solvent under a reducedpressure. Resulting oil was applied to a silica gel column and elutedwith chloroform/methanol (200:1 to 100:1), to obtain 4.99 g of the titlecompound in a colorless amorphous form.

IR (KBr) cm⁻¹ : 1703, 1514, 1327, 1247, 1135, 600;

NMR (CDCl₃) δ ppm: 2.10-2.45 (5H, m), 2.26 (6H, s), 2.45-2.85 (5H, m),3.20-3.65 (6H, m), 3.73 (3H, s), 4.00 (1H, m), 5.10 (2H, s), 6.53 (2H,d, J=8.79 Hz), 6.83 (2H, d, J=8.79 Hz), 7.34 (5H, s), 7.56 (1H, dd,J=8.05, 7.57 Hz), 8.10 (1H, d, J=8.05 Hz), 8.31 (1H, d, J=6.10 Hz), 8.35(1H, d, J=7.57 Hz), 8.59 (1H, d, J=6.10 Hz), 9.25 (1H, s).

EXAMPLE 138N-(2-Acetoxyethyl)-N-[2-(4-benzyloxycarbonylpiperazinyl)-1-(p-methoxybenzyl)ethyl]-5-isoquinolinesulfonamide

1.0 g of the product obtained in Example 73 was dissolved in 5 ml oftetrahydrofuran, to the solution were added 220 mg of ethylene glycolmonoacetate and 685 mg of triphenylphosphine in place ofN-tert-butoxycarbonylethanolamine, according to the procedure described:n Example 136, to obtain 600 mg of the title compound in a colorlessamorphous form.

NMR (CDCl₃) δ ppm: 2.04 (3H, s), 2.20-2.45 (5H, m), 2.60-2.80 (3H, m),3.20-3.40 (4H, m), 3.45-3.73 (2H, m), 3.74 (3H, s), 4.04 (1H, m), 4.27(2H, t, J=6.84 Hz), 5.10 (2H, s), 6.54 (2H, d, J=8.55 Hz), 6.82 (2H, d,J=8.55 Hz), 7.34 (5H, s), 7.59 (1H, dd, J=8.05, 7.57 Hz), 8.13 (1H, d,J=8.05 Hz), 8.30 (1H, d, J=6.10 Hz), 8.36 (1H, d, J=7.57 Hz), 9.27 (1H,s).

EXAMPLE 139N-[2-(4-Benzyloxycarbonylpiperazinyl)-1-(p-methoxybenzyl)ethyl}-N-(2-hydroxyethyl)-5-isoquinolinesulfonamide

600 mg of the amorphous compound obtained in Example 138 was dissolvedin 6 ml of methanol and 3 ml of tetrahydrofuran, to the solution wasadded 6 ml of 1N sodium hydroxide aqueous solution, and the mixture wasstirred at a room temperature for 2 hours. The reaction mixture wasdiluted with water and extracted twice with 50 ml of chloroform, and theextract was washed with saturated sodium chloride aqueous solution,dried over magnesium sulfate and evaporated to remove the solvent undera reduced pressure. Resulting oil was applied to a silica gel column andeluted with chloroform/methanol (100:1 to 50:1) to obtain 403 mg of thetitle compound in a colorless amorphous form.

IR (KBr) cm⁻¹ : 1701, 1514, 1433, 1332, 1249, 1136;

NMR (CDCl₃) δ ppm: 2.10-2.25 (3H, m), 2.25-2.50 (4H, m), 2.50-2.70 (1H,m), 3.10-3.45 (5H, m), 3.55-3.75 (2H, m), 3.76 (3H, s), 4.00-4.20 (2H,m), 5.08 (2H, s), about 5.4 (1H, br), 6.70 (2H, d, J=8.79 Hz), 6.79 (2H,d, J=8.79 Hz), 7.32 (5H, s), 7.73 (1H, dd, J - 8.30, 7.32 Hz), 8.22 (1H,d, J=8.3 Hz), 8.50 (1H, d, J=7.32 Hz), 8.63 (1H, d, J=6.10 Hz), 8.72(1H, d, J=6.10 Hz), 9.34 (1H, s).

EXAMPLE 140N-{2-[4-(3,4-Dichlorobenzylamino)piperidino]-1-(p-methoxybenzyl)ethyl}-N-methyl-5-isoquinolinesulfonamide

The amorphous compound obtained in Example 94 was subjected to alkalinehydrolysis, methylation with methyl iodide and potassium carbonate indimethylformamide/tetrahydrofuran (1:1), and reflux with 3N hydrochloricacid, to obtainN-{1-(p-methoxybenzyl)2-(4-oxopiperidino)ethyl}-N-methyl-5-isoquinolinesulfonamidein a colorless amorphous form.

NMR (CDCl₃) δ ppm: 2.37 (4H, t, J=5.99 Hz), 2.40-2.90 (8H, m), 2.94 (3H,s), 3.74 (3H, s), 4.23 (1H, m), 6.51 (2H, d, J=8.55 Hz), 6.83 (2H, d,J=8.55 Hz), 7.55 (1H, dd, J=8.32, 7.50 Hz), 8.10 (1H, d, J=8.32 Hz),8.19 (1H, d, J=7.50 Hz), 8.19 (1H, d, J=6.10 Hz), 8.55 (1H, d, J=6.10Hz), 9.25 (1H, s).

3.34 g of this compound was dissolved in 30 ml of methanol, to thesolution were added 1.89 g of 3,4-dichlorobenzylamine and 0.6 ml ofacetic acid, and the mixture was stirred at a room temperature for 3hours. The reaction mixture was cooled in a ice bath, and after adding450 mg of sodium cyanoborohydride, stirred with ice cooling for 30minutes and then at a room temperature for one hour. This reactionmixture was alkalized with sodium bicarbonate and extracted twice with150 ml of chloroform, and the extract was dried over magnesium sulfateand evaporated to remove the solvent under a reduced pressure. Resultingoil was applied to a silica gel column and eluted withchloroform/methanol (100:1 to 50:1), to obtain 2.78 g of the titlecompound in a colorless amorphous form.

IR (KBr) cm⁻¹ : 1514, 1327, 1249, 1157, 1130, 826, 600;

NMR (CDCl₃) δ ppm: 1.05-1.40 (2H, m), 1.60-2.15 (4H, m), 2.30-2.90 (8H,m), 2.93 (3H, s), 3.73 (5H, s), 4.13 (1H, m), 6.49 (2H, d, J=8.79 Hz),6.83 (2H, d, J=8.79 Hz), 7.15 (1H, dd, J=8.20, 1.95 Hz), 7.38 (1H, d,J=8.20 Hz), 7.44 (1H, d, J=1.95 Hz), 7.56 (1H, dd, J=8.06, 7.57 Hz),8.08 (1H, d, J=8.06 Hz), 8.19 (1H, d, J=6.35 Hz), 8.29 (1H, d, J=7.57Hz), 8.55 (1H, d, J=6.35 Hz), 9.23 (1H, s).

EXAMPLE 141N-2-{4-[N-(3,4-Dichlorobenzyl)-N-methylamino]piperidino}-1-p-methoxybenzyl)ethyl]]-N-methyl-5-isoquinolinesulfonamide

1.62 g of the amorphous compound obtained in Example 140 was dissolvedin 10 ml of tetrahydrofuran and 10 ml of dimethylformamide, to thesolution was added 115 mg of 60% sodium hydride with stirring under icecooling, and the mixture was allowed to react at the same temperaturefor 5 minutes and then at a room temperature for 15 minutes and againice-cooled. After adding 405 mg of methyl iodide, the mixture wasallowed to react at the same temperature for 5 minutes and then at aroom temperature for 2 hours, and poured to water. The mixture wasextracted with 200 ml of ethyl acetate, and the extract was washed witha saturated sodium chloride aqueous solution, dried over magnesiumsulfate and evaporated to remove the solvent under a reduced pressure.Resulting oil was applied to a silica gel column and eluted withchloroform/methanol (200:1 to 100:1) to obtain 880 mg of the titlecompound in a colorless amorphous form.

IR (KBr) cm⁻¹ : 1514, 1329, 1249, 1157, 1131, 826, 600;

NMR (CDCl₃) δ ppm: 1.10-2.10 (6H, m), 2.14 (3H, s), 2.20-3.00 (7H, m),2.93 (3H, s), 3.46 (2H, s), 3.73 (3H, s), 4.12 (1H, m),6.51 (2H, d,J=8.55 Hz), 6.85 (2H, d, J=8.55 Hz), 7.15 (1H, dd, J=8.30, 1.71 Hz),7.37 (1H, d, J=8.30 Hz), 7.42 (1H, d, J=1.71 Hz), 7.56 (1H, t, J=7.82Hz), 8.08 (1H, d, J=7.82 Hz), 8.20 (1H, d, J=6.11 Hz), 8.30 (1H, d,J=7.82 Hz), 8.56 (1H, d, J=6.11 Hz), 9.23 (1H, s).

REFERENCE EXAMPLE 39 4-Chlorocinnamyl alcohol

25.9 g of p-chlorocinnamic acid was dissolved in 250 ml of methanol, tothe solution was added 1.5 ml of concentrated sulfuric acid, and themixture was refluxed for 2 hours. The reaction mixture was poured onice, and the mixture was alkalized with sodium bicarbonate and extractedtwice with 1000 ml of chloroform. The extract was washed with asaturated sodium chloride aqueous solution, dried over magnesium sulfateand evaporated to remove the solvent under a reduced pressure, andresulting residue was applied to a silica gel column and eluted withhexane/ethyl acetate (10:1), to obtain 26.5 g of the methylp-chlorocinnamate.

This compound was dissolved in 250 ml of toluene, to the solution wasadded 200 ml of 1.5M diisobutyl aluminum hydride in toluene withstirring under ice cooling, and the mixture was stirred for 2 hours. Thereaction mixture was poured on ice, acidified with concentratedhydrochloric acid, and extracted twice with 700 ml of benzene. Theextract was washed with a saturated sodium chloride aqueous solution,dried over magnesium sulfate and evaporated to remove the solvent undera reduced pressure, and resulting residue was applied to a silica gelcolumn and eluted with hexane/ethyl acetate (4:1), to obtain 21.0 g ofthe title compound as colorless crystals,

¹ H-NMR (CDCl₃, δ ppm): 4.33 (2H, brs), 6.33 (1H, dt, J=17.1, 5.7 Hz),6.59 (1H, dt, J=17.1, 2.0 Hz), 7.29 (4H, s).

REFERENCE EXAMPLE 40 N-4-Chlorocinnamyl-1,2-phenylenediamine

11.9 g of the crystals obtained in Reference Example 39 was dissolved in120 ml of chloroform, to the solution was added 10.1 g of thionylchloride with stirring in an ice bath, and after removing from the icebath, the mixture was stirred for one hour while allowing the reactiontemperature to rise up to a room temperature. Chloroform and excessthionyl chloride were evaporated off under a reduced pressure, to theresidue was added benzene, and the solvent was evaporated off under areduced pressure. Resulting residue was applied to a silica gel columnand eluted with hexane/ethyl acetate (15:1), to obtain 11.3 g of4-chlorocinnamyl chloride as colorless crystals.

¹ H-NMR (CDCl₃, δ ppm): 4.23 (2H, dd, J=6.3, 1.0 Hz), 6.29 (1H, dt,J=16.6, 6.9 Hz), 6.62 (1H, dt, J=16.6, 1.0 Hz), 7.30 (4H, s).

19.6 g of 1,2-phenylenediamine was dissolved in 300 ml ofdimethylformamide, to the solution were added 11.3 g of theabove-prepared 4-chlorocinnamyl chloride crystals and 12.5 g ofpotassium carbonate at a room temperature with stirring, and the mixturewas stirred for 48 hours under the same condition. After adding waterand sodium chloride, the reaction mixture was extracted twice with 1000ml of chloroform, and the extract was dried over magnesium sulfate andevaporated to remove the solvent under a reduced pressure. Resultingresidue was applied to a silica gel column and eluted with hexane/ethylacetate (3:1), to obtain 12.85 g of the title compound as colorlesscrystals.

¹ H-NMR (CDCl₃, δ ppm): 3.4 (3H, brs), 3.93 (2H, dd, J=5.71, 1.0 Hz),6.36 (1H, dt, J=16.0, 5.71 Hz), 6.59 (1H, dt, J=16.0, 1.0 Hz), 6.68-6.9(4H, m), 7.28 (4H, s).

EXAMPLE 142N-[2-(4-Chlorocinnamylamino)phenyl]-5-isoquinolinesulfonamide

12.85 g of the crystals obtained in Reference Example 40 was dissolvedin 200 ml of pyridine, to the solution was added 15.1 g of5-isoquinolinesulfonyl chloride, hydrochloride with stirring in a icebath, and after removing from the ice bath, the mixture was allowed toreact at a room temperature for 18 hours. The reaction mixture waspoured on ice, alkalized with sodium bicarbonate and extracted twicewith 1000 ml o chloroform. The extract was dried over magnesium sulfateand the solvent was evaporated off under a reduced pressure to formscarcely soluble crystals. To the crystals was added chloroform, thewhole was refluxed and then cooled, and the resulting crystals wascollected by suction filtration, washed with chloroform and dried undera reduced pressure, to obtain 17.23 g of the title compound as colorlesscrystals.

Melting point: 205°-208° C. (decomposed);

IR (KBr) cm⁻¹ : 1600, 1320, 1150, 1135;

¹ H-NMR (CDCl₃ +CD₃ OD, δ ppm): 3.73 (2H, dd, J=5.62, 1.46 Hz), 6.04(1H, dt, J=15.8, 5.37 Hz), 6.27-6.35 (2H, m), 6.42 (1H, dt, J=16.11,1.46 Hz), 6.58 (1H, d, J=7.81 Hz), 7.04 (1H, ddd, J=8.30, 6.10, 2.93Hz), 7.25 (2H, d, J=9.03 Hz), 7.31 (2H, d, J=9.03 Hz), 7.63 (1H, dd,J=8.06, 7.33 Hz), 8.17 (1H, dd, J=7.32 , 0.98 Hz), 8.30 (1H, dd, J=7.57,1.23 Hz), 8.47 (1H, dd, J=6.35, 1.02 Hz), 8.55 (1H, d, J=6.35 Hz), 9.25(1H, d, J=0.98 Hz).

EXAMPLE 143 N-[2-(4-Chlorocinnamylamino)phenyl]-N-methyl-5-isoquinolinesulfonamide

380 mg of the crystals obtained in Example 142 was dissolved in 6 ml ofmethanol, to the solution was added 10 ml of a solution of diazomethanein ether at a room temperature with stirring, and the mixture wasstirred for 18 hours. The solvent was evaporated off under a reducedpressure to obtain an oil, which was then applied to a silica gel columnand eluted with hexane/ethyl acetate (1:1) to obtain acetate, which wasthen recrystallized from hexane/ethyl acetate to obtain 270 mg of thetitle compound as colorless crystals.

Melting point: 149°-151° C.;

IR (KBr) cm⁻¹ : 1595, 1325, 1125, 830, 745;

¹ H-NMR (CDCl₃, δ ppm): 3.24 (3H, s), 3.87 (2H, m), 4.81 (1H, t, J=5.71Hz), 6.13 (1H, dt, J=19.14, 5.71 Hz), 6.25-6.40 (2H, m), 6.53 (1H, dt,J=19.14, 1.0 Hz), 6.67 (1H, d, J=8.57 Hz), 7.05-7.18 (1H, m), 7.28 (4H,s), 7.67 (1H, t, J=7.42 Hz), 8.19 (1H, d, J=7.42 Hz), 8.28 (1H, d,J=6.28 Hz), 8.32 (1H, dd, J=7.42, 1.0 Hz), 8.51 (1H, d, J=6.28 Hz), 9.30(1H, d, (J=1.0 Hz).

EXAMPLE 1441-(4-Chlorocinnamyl)-4-(5-isoquinolinesulfonyl)-1,2,3,4-tetrahydroquinoxaline

5.0 g of the crystals obtained in Example 142 was dissolved in 75 ml ofdimethylformamide, to the solution was added 4.6 g of potassiumcarbonate and 2.19 g of 1,2-dibromoethane at a room temperature withstirring, and the mixture was stirred for 60 hours. The reaction mixturewas poured in water, saturated with sodium chloride, and extracted twicewith 400 ml of chloroform. The extract was dried over magnesium sulfate,evaporated to remove the solvent under a reduced pressure. Resultingresidue was applied to a silica gel column and eluted withchloroform/methanol (400:1) and then hexane/ethyl acetate (2:1), toobtain 3.32 g of the title compound in yellow amorphous form.

IR (KBr) cm⁻¹ : 1600, 1340, 1150, 1130, 660;

¹ H-NMR (CDCl₃, δ ppm): 2.68 (2H, t, J=5.71 Hz), 3.49 (2H, dd, J=6.28,1.0 Hz), 3.89 (2H, t, J=5.71 Hz), 5.43 (1H, dt, J=15.42, 6.28 Hz), 6.10(1H, dt, J=15.42, 1.0 Hz), 6.48 (1H, dd, J=7.99, 1.0 Hz), 6.75 (1H, dt,J=7.99, 1.0 Hz), 7.09 (2H, d, J=7.99 Hz), 7.12 (1H, dt, J=7.99, 1.0 Hz),7.31 (2H, d, J=7.99 Hz), 7.54 (1H, dd, J=7.99, 1.0 Hz), 7.59 (1H, t,J=7.99 Hz), 7.77 (1H, d, J=6.28 Hz), 7.94 (1H, d, J=7.99 Hz), 8.30 (1H,d, J=6.28 Hz), 8.38 (1H, dd, J=7.99, 1.0 Hz), 9.03 (1H, d, J=1.0 Hz).

EXAMPLE 145

The same procedure as described in Example 142 was repeated except thatN-[3-(3-pyridyl)allyl]-1,2-phenylenediamine was used in place ofN-(4-chlorocinnamyl)-1,2-phenylenediamine, to obtainN-{2-[3-(3-pyridyl)allylamino]phenyl}-5-isoquinolinesulfonamide in abrown amorphous form.

¹ H-NMR (CDCl₃, δppm): 2.2 (1H, br), 3.78 (2H, dd, J=5.14, 1.0 Hz), 4.85(1H, br), 6.14 (1H, dt, J=15.99, 5.14 Hz), 6.33 (2H, d, J=4.57 Hz), 6.42(1H, dt, J=15.99, 1.0 Hz), 6.58 (1H, d, J=7.42 Hz), 6.98-7.15 (1H, m),7.26 (1H, dd, J=7.42, 4.57 Hz), 7.59 (1H, t, J=7.42 Hz), 7.65 (1H, dt,J=7.42, 1.0 Hz), 8.16 (1H, d, J=7.99 Hz), 8.30 (1H, d, J=6.85 Hz),8.35-8.53 (3H, m), 8.56 (1H, d, J=6.28 Hz), 9.32 (1H, s).

EXAMPLE 146

The amorphous compound obtained in Example 145 was treated according tothe procedure in Example 143 to obtainN-{2-[3-(3-pyridyl)allylamino)phenyl}-N-methyl-5-isoquinolinesulfonamide.

¹ H-NMR (CDCl₃, δ ppm): 3.24 (3H, s), 3.92 (2H, t, J=4.57 Hz), 4.90 (1H,t, J=5.71 Hz), 6.26 (1H, dt, J=15.42, 5.14 Hz), 6.32 (2H, d, J=4.57 Hz),6.58 (1H, dt, J=15.42, 1.0 Hz), 6.62-6.74 (2H, m), 7.05-7.20 (1H, m),7.26 (1H, dd, J=7.99, 4.57 Hz), 7.6-7.75 (1H, m), 8.21 (1H, d, J=7.99Hz), 8.28 (1H, d, J=6.85 Hz), 8.32 (1H, d, J=6.28 Hz), 8.47 (1H, dd,J=5.71, 1.0 Hz), 8.51 (1H, d, J=6.28 Hz), 8.58 (1H, d, J=1.7 Hz), 9.31(1H, s).

REFERENCE EXAMPLE 41 2-Amino-3-(4-chlorocinnamylamino pyridine

7.71 g of p-chlorocinnamyl chloride and 13.5 g of 2,3-diaminopyridinewere dissolved in 220 ml of dimethylformamide, and to the solution wasadded 8.6 g of potassium carbonate, and the mixture was stirred at aroom temperature for 50 hours, and after adding 300 ml of water,extracted twice with 200 ml of chloroform. The extract was dried overmagnesium sulfate and concentrated under a reduced pressure, andresulting residue was applied to a silica gel column and eluted withchloroform/methanol (100:1 to 50:1), to obtain 4.52 g of the titlecompound as yellow crystals.

¹ H-NMR (CDCl₃, δ ppm): 3.38 (1H, br), 3.92 (2H, m), 4.20 (2H, br), 6.31(1H, dt, J=16.1, 5.9 Hz), 6.59 (1H, dt, J=16.1, 1.5 Hz), 6.71 (1H, dd,J=4.9, 7.8 Hz), 6.86 (1H, dd, J=1.5, 7.8 Hz), 7.29 (4H, s), 7.63 (1H,dd, J=1.5, 4.9 Hz).

EXAMPLE 1473-(4-Chlorocinnamylamino)-2-(5-isoquinolinesulfonylamino)pyridine

4.52 g of the crystals obtained in Reference Example 41 was dissolved in50 ml of pyridine, to the solution were added 5.8 g of5-isoquinolinesulfonyl chloride hydrochloride and 3 g ofdimethylaminopyridine, and the mixture was stirred for 18 hours at aroom temperature, after adding 150 ml of water, extracted twice with 80ml of chloroform. The extract was dried over magnesium sulfate andconcentrated under a reduced pressure, and resulting residue was appliedto a silica gel column and eluted with chloroform/methanol (100:1), andresulting crystals was washed with ethyl acetate, to obtain 1.2 g of thetitle compound as yellow crystals.

Melting point: 211°-217° C. (decomposed);

IR (KBr) cm⁻¹ : 1595, 1550, 1345, 1285, 1250, 1105;

¹ H-NMR (CDCl₃, δ ppm): 3.89 (2H, m), 5.45 (1H, t, J=5.9 Hz), 6.12 (1H,dt, J=16.1, 5.4 Hz), 6.45 (1H, d, J=16.1 Hz), 6.51-6.62 (2H, m), 6.92(1H, brs), 7.21 (2H, d, J=8.8 Hz), 7.29 (2H, d, J=8.8 Hz), 7.64 (1H, dd,J=7.3, 8.3 Hz), 8.12 (1H, d, J=8.3 Hz), 8.45 (1H, dd, J=1.0, 7.3 Hz),8.64 (1H, d, J=5.9 Hz), 8.69 (1H, d, J=5.9 Hz), 9.31 (1H, s).

REFERENCE EXAMPLE 42 Methyl 4-amino-3-(4-chlorocinnamylamino)benzoate

5.0 g of methyl 3,4-diaminobenzoate was dissolved in 40 ml ofdimethylformamide, and to the solution were added 2.07 g of potassiumcarbonate and 1.87 g of p-chlorocinnamyl chloride, and reaction wascarried out according to the procedure in Reference Example 40, toobtain 2.0 g of the title compound as a light brown oil.

NMR (CDCl₃) δ ppm: 3.85 (3H, s), 3.94 (2H, brd), 6.35 (1H, dt, J=5.86,15.8 Hz), 6.59 (1H, d, J=5.8 Hz), 6.7 (1H, d, J=8.02 Hz), 7.28 (4H, s),7.4 (1H, d, J=1.4 Hz), 7.46 (1H, dd, J=1.4, 8.0 Hz).

EXAMPLE 148 Methyl4-(5-isoquinolinesulfonamino)-3-(4-chlorocinnamylamino)benzoate

1.8 g of the oil obtained in Reference Example 42 was dissolved in 18 mlof pyridine, to the solution was added 1.29 g of 5-isoquinolinesulfonylchloride hydrochloride with stirring under ice cooling, and the mixturewas treated according to the procedure in Example 142 to obtain residue,which was then applied to a silica gel column and eluted withchloroform/methanol (100:1), to obtain 1.28 g of the title compound aslight yellow crystals.

Melting point: 143°-145° C. (subliming at a higher temperature thanmelting point);

NMR (CDCl₃) δ ppm: 3.78 (2H, brd), 3.82 (3H, s), 6.0 (1H, dt, J=5.86,15.87 Hz), 6.4 (1H, d, J=15.8 Hz), 6.45 (1H, d, J=8.3 Hz), 7.05 (1H dd,J=1.8, 8.3 Hz), 7.2-7.3 (5H, brs}, 7.60 (1H, t, J=7.6 Hz), 8.15 (1H, d,J=8.3 Hz), 8.29 (1H, dd, J=1.2, 7.3 Hz), 8.43 (1H, d, J=6.1 Hz), 8.61(1H, d, J=6.1 Hz), 9.3 (1H, d, J=1.2 Hz).

REFERENCE EXAMPLE 43 N-Cinnamyl-1,2-phenylenediamine

3.24 g of ortho-phenylenediamine was dissolved in 30 ml ofdimithylformaide, to the solution were added 2.07 g of potassiumcarbonate and 1.52 g of cinnamyl chloride, and the mixture was stirredovernight at a room temperature. After adding 100 ml of water, thereaction mixture was extracted twice with 100 ml and 50 ml ofchloroform, and the extract was washed with a saturated sodium chlorideaqueous solution, dried over magnesium sulfate and evaporated to removethe solvent under a reduced pressure. The resulting residue was appliedto a silica gel column and eluted with chloroform, to obtain 2.0 g ofthe title compound as light brown crystals.

Melting point: 59°-66° C. (decomposed);

NMR (CDCl₃) δ ppm: 3.3 (2H, brs), 3.93 (2H, brd), 6.4 (1H, d and t,J=5.6, 16.1 Hz), 6.1-6.45 (4H, complex) 5.2-5.7 (5H, complex).

EXAMPLE 149 N-(2-Cinnamylamino)phenyl-5-isoquinolinesulfonamide

1.8 g of the crystals obtained in Reference Example 43 was dissolved in18 ml of pyridine, to the solution was added 1.83 g ofisoquinolinesulfonyl chloride hydrochloride, and the mixture was stirredfor 18 hours at a room temperature. After adding 50 ml of water, thereaction mixture was extracted twice with 80 ml of chloroform, and theextract was washed with a saturated sodium chloride aqueous solution,dried over magnesium sulfate and evaporated to remove the solvent undera reduced pressure. The resulting residue was applied to a silica gelcolumn and eluted with chloroform/methanol (100:1), to obtain 2.40 g ofthe title compound as pale reddish crystals.

Melting point: 181°-185° C.;

NMR (CDCl₃) δ ppm: 3.75 (2H, brd), 4.55 (1H, brs), 6.05 (1H, d and t,J=5.6, 16.1 Hz), 6.35 (2H, brd), 6.45 (1H, d, J=16.1 Hz) 6.63 (1H, d,J=8.3 Hz), 7-7.13 (1H, complex), 7.25-7.4 (5H, complex), 7.6 (1H, t,J=8.2 Hz), 8.15 (1H, d, J=8.3 Hz), 8.31 (1H, dd, J=1.0, 8.2 Hz), 8.4(1H, d, J=6.6 Hz), 8.65 (1H, d, J=6.6 Hz), 9.3 (1H, d, J=1.0 Hz).

REFERENCE EXAMPLE 44 N-(4-Chlorocinnamyl)-1,3-phenylenediamine

3.24 g of metha-phenylenediamine was dissolved in 40 ml ofdimethylformamide, to the solution were added 2.07 g of potassiumcarbonate and 1.87 g of p-chlorocinnamyl chloride, and the mixture wassubjected to react according to the procedure in Reference Example 40.The resulting residue was applied to a silica gel column and eluted withn-hexane/ethyl acetate (3:1 to 2:1), to obtain 1.70 g of the titlecompound as a light brown oil.

NMR (CDCl₃) δ ppm: 3.65 (2H, brs), 3.90 (2H, dd, J=1.4, 5.6 Hz), 6.0-6.2(3H, complex), 6.3 (1H, dd, J=5.6, 15.9 Hz), 6.56 (1H, dd, J=1.4, 15.9Hz), 6.97 (1H, t, J=8.1 Hz), 7.3 (4H, s).

EXAMPLE 150 N-3-(4-Chlorocinnamylamino)phenyl]-5-isoquinolinesulfonamide

1.7 g of the oil obtained in Reference Example 44 was dissolved in 18 mlof pyridine, to the solution was added 1.99 g of 5-isoquinolinesulfonylchloride.HCl with stirring under a ice cooling, and the same procedureas described in Example 142 was repeated to obtain 1.45 g of the titlecompound as a light brown oil.

NMR (CDCl₃)δ ppm: 3.8 (2H, brd), 3.92 (1H, brs), 6.15 (1H, d and t,J=5.6, 15.9 Hz), 6.25 (1H, brs), 6.35 (2H, brd), 6.49 (1H, d, J=15.9Hz), 6.92 (1H, t, J=8.1 Hz), 7.3 (4H, s), 7.51 (1H, t, J=8.3 Hz), 8.1(1H, d, J=8.3 Hz), 8.35 (1H, dd, J=1.0, 8.3 Hz), 8.45 (1H, d, J=6 1 Hz),8.65 (1H, d, J=6.4 Hz), 9.3 (1H, d, J=1.0 Hz).

EXAMPLE 151N-{2-(p-Chlorocinnamylamino)phenyl}-N-(2-hydroxyethyl)-5-isoquinolinesulfonamide

1.5 g of the crystals obtained in Example 142 was dissolved in 8 ml oftetrahydrofuran, to the solution were added 1.32 g of triphenylphosphineand 420 mg of ethylene glycol monoacetate, and also added dropwise asolution of 1.01 g of diisopropyl azodicarboxylate in 2 ml oftetrahydrofuran with stirring in a ice bath. After being removed fromthe ice bath, the mixture was warmed to a room temperature, stirred for3 hours, diluted with ethyl acetate and extracted twice with 70 ml of 2Nhydrochloric acid. The aqueous layer was alkalized with sodiumbicarbonate and extracted twice with 150 ml of chloroform, and theextract was dried over magnesium sulfate and evaporated under a reducedpressure to remove the solvent. Resulting oily residue was dissolved in20 ml of methanol and 20 ml of tetrahydrofuran, to the solution wasadded 20 ml of 1N sodium hydroxide aqueous solution, and the reactionwas carried out at a room temperature for 2 hours. The reaction mixturewas diluted with water and extracted twice with 100 ml and 50 ml each ofchloroform, and the extract was dried over magnesium chloride andevaporated under a reduced pressure to remove the solvent. The resultingoil was applied to a silica gel column and eluted withchloroform/methanol (100:1 to 50:1), to obtain 1.59 g of the titlecompound in a yellow amorphous form.

IR (KBr) cm⁻¹ =1603, 1516, 1491, 1342, 1161, 1139, 835, 758, 604, 509;

NMR (CDCl₃) δ ppm: 3.09 (1H, m), 3.29 (1H, ddd, J=13.43, 4.64, 3.18 Hz),3.47 (1H, m), 3.75 (1H, m), 3.85 (2H, m), 4.33 (1H, ddd, J=13.43, 8.30,4.15 Hz), 5.12 (1H, m), 6.16 (1H, dt, J=15.87, 5.62 Hz), 6.23 (1H, dd,J=8.06, 1.47 Hz), 6.40 (1H, td, J=7.33, 1.47 Hz), 6.55 (1H, d, J=16.11Hz), 6.76 (1H, d, J=8.54 Hz), 7.15 (1H, t, J=8.30 Hz), 7.29 (4H, s),7.63 (1H, t, J=8.30 Hz), 8.18 (1H, d, J=8.30 Hz), 8.28 (1H, d, J=8.30Hz), 8.28 (1H, d, J=6.35 Hz), 8.52 (1H, d, J=6.3 Hz), 9.31 (1H, s).

EXAMPLE 152N-{2-(p-Chlorocinnamylamino)phenyl}-N-(2-dimethylaminoethyl)-5-isoquinolinesulfonamide

2.0 g of the crystals obtained in Example 142 was dissolved in 10 ml oftetrahydrofuran, to the solution were added 1.75 g of triphenylphosphineand 520 mg of N,N-dimethyl ethanolamine, and thereto added dropwise asolution of 1.3 g of diisopropyl azodicarboxylate in 3 ml of beingtetrahydrofuran with stirring in ice bath. After being removed from theice bath, the mixture was warmed to a room temperature, stirred for 3hours, and then diluted with ethyl acetate, and extracted twice with 100ml of 2 N hydrochloric acid. The extract was alkalized with a sodiumbicarbonate aqueous solution and extracted twice with 200 ml ofchloroform. The extract was dried over magnesium sulfate and evaporatedunder a reduced pressure to remove the solvent, and a resulting oil wasapplied to a silica gel column and eluted with chloroform/methanol(100:1), to obtain 1.35 g of the title compound in a yellow amorphousform.

IR (KBr) cm⁻¹ : 1603, 1521, 1491, 1458, 1329, 1160, 1137, 834, 749, 601,507;

NMR (CDCl₃) δ ppm: 2.19 (6H, s), 2.15-2.55 (2H, m), 3.19 (1H, dt,J=12.69, 4.15 Hz), 3.56 (2H, m), 4.35 (1H, m), 5.78 (1H, m), 5.89 (1H,dt, J=15.87, 5.37 Hz), 6.30-6.55 (3H, m), 6.64 (1H, dd, J=7.81, 1.71Hz), 7.09 (1H, td, J=7.81, 1.71 Hz), 7.23 (2H, d, J=9.03 Hz), 7.30 (2H,d, J=9.03 Hz), 7.57 (1H, dd, J=8.30, 7.57 Hz), 8.11 (1H, d, J=8.30 Hz),8.24 (1H, d, J=7.57 Hz), 8.40 (1H, d, J=6.35 Hz), 8.53 (1H, d, J=6.35Hz), 9.26 (1H, s).

EXAMPLES 153 TO 171

In Example 153 to 171 the following general reaction was used. ##STR22##

EXAMPLE 153 (n=2, Aryl=4-chlorophenyl)N-[2-(4-Chloro-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

7.30 g of N-(2-aminoethyl)-5-isoquinolinesulfonamide was dissolved in150 ml of methanol, to the solution was added 6.30 g ofp-chlorobenzalacetone, and the mixture was stirred at a room temperaturefor 36 hours. After addition of 1.32 g of sodium tetrahydrideborate withice-water cooling, the mixture was stirred for 30 minutes. The reactionmixture was concentrated to half of original volume under a reducedpressure, and after adding 300 ml of ethyl acetate, washed three timeswith water. The aqueous layer was extracted with 100 ml of ethylacetate, and the extract was washed with water as described above. Theethyl acetate layers were combined, washed twice with a saturated sodiumchloride aqueous solution, dried over magnesium sulfate, filtered, andevaporated under a reduced pressure to remove the solvent. The resultingresidue was purified using a silica gel column (silica gel: 200 g;eluant: 5% methanol in chloroform), to obtain 6.78 g of the titlecompound in a colorless amorphous form, while recovering the residualstarting material.

¹ H-NMR (CDCl₃, δ ppm): 1.06 (3H, d, J=6.6 Hz), 1.8-2.8 (2H, br),2.57-2.64 (2H, m), 2.96 (2H, t, J=5.7 Hz), 3.06 (1H, dq, J=7.8, 6.6 Hz),5.79 (1H, dd, J=15.8, 7.8 Hz), 6.24 (1H, d, J=15.8 Hz), 7.19 (2H, dm,J=8.8 Hz), 7.25 (2H, dm, J=8.8 Hz), 7.67 (1H, dd, J=8.0, 7.6 Hz), 8.28(1H, dt, J=8.0, 1.0 Hz), 8.42-8.46 (2H, m), 8.69 (1H, d, J=6.1 Hz), 9.35(1H, d, J=1.0 Hz).

EXAMPLE 154 (n=2, Aryl=phenyl)N-[2-(α-Methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NHR (CDCl₃, δ ppm): 2.0-3.0 (2H, br), 2.59-2.66 (2H, m), 2.98 (2H,t, J=5.5 Hz), 3.09 (1H, dq, J=8.0, 6.6 Hz), 5.80 (1H, dd, J=15.9, 8.0Hz), 6.28 (1H, d, J=15.9 Hz), 7.28 (5H, brs), 7.66 (1H, dd, J=8.3, 7.3Hz), 8.17 (1H, brd, J=8.3 Hz), 8.43 (1H, dd, J=7.3, 1.2 Hz), 8.44 (1H,d, J=6.1 Hz), 8.68 (1H, d, J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).

EXAMPLE 155 (n=2, Aryl=2,4-difluorophenyl)N-[2-(2,4-Difluoro-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.06 (3H, d, J=6.4 Hz), 1.3-2.2 (2H, br),2.57-2.67 (2H, m), 2.96 (2H, t, J=5.6 Hz), 3.04 (1H, dq, J=8.0, 6.4 Hz),5.81 (1H, dd, J=16.1, 8.0 Hz), 6.35 (1H, d, J=16.1 Hz), 6.79 (1H, d,J=8.3 Hz and 1H, ddd, J=17.6, 8.8, 2.0 Hz), 7.30 (1H, ddd, J=14.9, 8.3,2.0 Hz), 7.69 (1H, dd, J=8.3, 7.3 Hz), 8.29 (1H, dt, J=8.3, 1.0 Hz),8.42-8.47 (2H, m), 8.70 (1H, d, J=6.1 Hz), 9.35 (1H, d, J=1.0 Hz).

EXAMPLE 156 (n=2, Aryl=2,4-dichlorophenyl)N-2-(2,4-Dichloro-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.07 (3H, d, J=6.6 Hz), 1.5-2.5 (2H, br),2.58-2.65 (2H, m), 2.97 (2H, t, J=5.5 Hz), 3.09 (1H, dq, J=8.0, 6.6 Hz),5.75 (1H, dd, J=15.8, 8.0 Hz), 6.58 (1H, d, J=15.8 Hz), 7.18 (1H, dd,J=8.5, 2.0 Hz), 7.28 (1H, d, J=8.5 Hz), 7.35 (1H, d, J=2.0 Hz), 7.68(1H, dd, J=8.0, 7.3 Hz), 8.18 (1H, td, J=8.0, 1.0 Hz), 8.42-8.47 (2H,m), 8.70 (1H, d, J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).

EXAMPLE 157 (n=2, Aryl=3-chlorophenyl)N-[2-(3-Chloro-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.06 (3H, d, J=6.6 Hz), 1.3-2.4 (2H, br),2.56-2.63 (2H, m), 2.97 (2H, t, J, 5.6 Hz), 3.06 (1H, dq, J=7.8, 6.6Hz), 5.80 (1H, dd, J=15.9, 7.8 Hz), 6.22 (1H, d, J=15.9 Hz), 7.10-7.26(4H, m), 7.68 (1H, dd, J=8.1, 7.5 Hz), 8.18 (1H, dt, J=8.1, 1.0 Hz),8.42-8.47 (2H, m), 8.70 (1H, d, J=6.1 Hz), 9.35 (1H, d, J=1.0 Hz).

EXAMPLE 158 (n=2, Aryl=2-nitrophenyl)N-[2-(α-Methyl-2-nitrocinnamylamino)ethyl]-5-isoquinolinesulfonamide

Light yellow amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.08 (3H, d, J=6.4 Hz), 1.3-2.6 (2H, br),2.61-2.67 (2H, m), 2.99 (2H, t, J=5.6 Hz), 3.09 (1H, dq, J=7.8, 6.4 Hz),5.73 (1H, dd, J=15.6, 7.8 Hz), 6.73 (1H, d, J=15.6 Hz), 7.36-7.56 (3H,m), 7.68 (1H, dd, J=8.3, 7.3 Hz), 7.92 (1H, dd, J=7.9, 1.2 Hz),8.42-8.47 (2H, m), 8.67 (1H, d, J=6.1 Hz), 9.31 (1H, d, J=1.0 Hz).

EXAMPLE 159 (n=2, Aryl=4-nitrophenyl)N-[2-(α-Methyl-4-nitrocinnamylamino)ethyl]-5-isoquinolinesulfonylamide

Light yellow amorphous form;

¹ H-NMR (CDCl₃ , δ ppm): 1.10 (3H, d, J=6.6 Hz), 1.4-2.6 (2H, br),2.60-2.67 (2H, m), 2.99 (2H, t, J=5.5 Hz), 3.14 (1H, dq, J=7.6, 6.6 Hz),6.05 (1H, dd, J=15.9, 7.6 Hz), 6.38 (1H, d, J=15.9 Hz), 7.40 (2H, dm,J=8.8 Hz), 7.69 (1H, dd, J=8.3, 7.5 Hz), 8.14 (2H, dm, J=8.8 Hz), 8.23(1H, brd, J=8.3 Hz), 8.43-8.48 (2H, m), 8.68 (1H, d, J=6.1 Hz), 9.36(1H, d, J=1.0 Hz).

EXAMPLE 160 (n=2, Aryl=4-methylphenyl)N-[2-(α,4-Dimethylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.05 (3H, d, J=6.6 Hz), 2.0-2.5 (2H, br), 2.33(3H, s), 2.56-2.64 (2H, m), 2.96 (2H, t, J=5.9 Hz), 3.05 (1H, m), 5.73(1H, dd, J=15.9, 7.8 Hz), 6.24 (1H, d, J=15.9 Hz), 7.09 (2H, brd, J=8.3Hz), 7.16 (2H, brd, J=8.3 Hz), 7.67 (1H, t, J=8.0 Hz), 8.17 (1H, brd,J=8.0 Hz), 8.43 (1H, d, J=8.0 Hz), 8.44 (1H, d, J=6.1 Hz), 8.68 (1H, d,J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).

EXAMPLE 161 (n=2, Aryl=3,4-methylenedioxyphenyl)N-[2-(α-Methyl-3,4-methylenedioxycinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δppm): 1.04 (3H, d, J=6.3 Hz), 2.56-2.63 (2 H, m), 2.95(2H, t, J=5.6 Hz), 3.05 (1H, dq, J=8.0, 6.3 Hz), 5.60 (1H, dd, J=15.9,8.0 Hz), 5.95 (2H, s), 6.18 (1H, d, J=15.9 Hz), 6.70 (1H, dd, J=7.5, 1.5Hz), 6.73 (1H, d, J=7.5 Hz), 6.79 (1H, d, J=1.5 Hz), 7.68 (1H, dd,J=8.1, 7.5 Hz), 8.19 (1H, brd, J=8.1 Hz), 8.42-8.46 (2H, m), 8.69 (1H,d, J=6.1 Hz), 9.35 (1H, d, J=1.0 Hz).

EXAMPLE 162 (n=2, Aryl=2-pyridyl) N-{2-[1-Methyl-3-(2-pyridyl)-2-propenylamino]ethyl}-5-isoquinolinesulfonamide

¹ H-NMR (CDCl₃, δ ppm): 1.07 (3H, d, J=6.6 Hz), - 4.0 (2H, br), 2.62(2H, dt, J=5.7, 5.7 Hz), 2.97 (2H, t, J=6.4 Hz), 3.06 (1H, dq, J=5.6,6.6 Hz), 6.35 (1H, d, J=5.6 Hz), 6.37 (1H, s), 7.12 (1H, dddd, J=7.8,5.0, 2.0, 1.0 Hz), 7.21 (1H, d, J=7.8 Hz), 7.62 (1H, td, J=7.8, 2.0 Hz),7.68 (1H, dd, J=8.0, 7.3 Hz), 8.18 (1H, brd, J=8.0 Hz), 8.44 (1H, d,J=7.3 Hz), 8.45 (1H, d, J=7.3 Hz), 8.52 (1H, ddd, J=5.0, 2.0, 1.0 Hz),8.67 (1H, d, J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).

EXAMPLE 163 (n=2, Aryl=4-pyridyl)N-{2-[1-Methyl-3-(4-pyridyl)-2-propenylamino]ethyl}-5-isoquinolinesulfonylamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.09 (3H, d, J=6.3 Hz), 1.2-1.9 (2H, br),2.59-2.65 (2H, m), 2.98 (2H, t, J=6.0 Hz), 3.12 (1H, dq, J=7.3, 6.3 Hz),6.06 (1H, dd, J=15.9, 7.3 Hz), 6.26 (1H, d, J=15.9 Hz), 7.14 (2H, dd,J=6.1, 1.5 Hz), 7.69 (1H, dd, J=8.1, 7.5 Hz), 8.19 (1H, brd, J=8.1 Hz),8.42-8.47 (2H, m), 8.51 (2H, dd, J=6.1, 1.5 Hz), 8.68 (1H, d, J=6.3 Hz),9.35 (1H, d, J=1.0 Hz).

EXAMPLE 164 (n=2, Aryl=2-thienyl)N-{2-[1-Methyl-3-(2-thienyl)-2-propenylamino]ethyl}-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.05 (3H, d, J=6.6 Hz), 1.2-2.5 (2H, br),2.56-2.64 (2H, m), 2.93-3.05 (3H, m), 5.65 (1H, dd, J=15.6, 8.0 Hz),6.41 (1H, d, J=15.6 Hz), 6.85 (1H, dd, J=3.7, 2.4 Hz), 6.94 (1H, dd,J=4.9, 3.7 Hz), 7.13 (1H, dd, J=4.9, 2.4 Hz), 7.68 (1H, dd, J=8.3, 7.5Hz), 8.19 (1H, brd, J=8.3 Hz), 8.42-8.46 (2H, m), 8.69 (1H, d, J=6.1Hz), 9.35 (1H, d, J=1.0 Hz).

EXAMPLE 165 (n=2, Aryl=2-furyl)N-{2-[3-(2-Furyl)-1-methyl-2-propenylamino]ethyl}-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.04 (3H, d, J=6.4 Hz), 1.3-1.5 (2H, br), 2.59(2H, td, J=6.0, 4.9 Hz), 2.95 (2H, t, J=6.0 Hz), 2.98 (1H, dq, J=7.8,6.4 Hz), 5.75 (1H, dd, J=15.9, 7.8 Hz), 6.10 (1H, d, J=15.9 Hz), 6.16(1H, d, J=3.2 Hz), 6.35 (1H, dd, J=3.2, 1.9 Hz), 7.32 (1H, d, J=1.9 Hz),7.68 (1H, dd, J=8.3, 7.5 Hz), 8.19 (1H, brd, J=8.3 Hz), 8.42-8.47 (2H,m), 8.69 (1H, d, J=6.1 Hz), 9.35 (1H, d, J=1.0 Hz).

EXAMPLE 166 (n=2, Aryl=4-fluorophenyl)N-[2-(4-Fluoro-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.06 (3H, d, J=6.4 Hz), 1.3-2.0 (2H, br),2.57-2.63 (2H, m), 2.95 (2H, t, J=5.5 Hz), 3.05 (1H, dq, J=8.0, 6.4 Hz),5.72 (1H, dd, J=15.9, 8.0 Hz), 6.25 (1H, d, J=15.9 Hz), 6.98 (2H, tm,J=8.7 Hz), 7.20-7.27 (2H, m), 7.68 (1H, dd, J=8.1, 7.3 Hz), 8.18 (1H,brd, J=8.1 Hz), 8.42-8.47 (2H, m), 8.69 (1H, d, J=6.1 Hz), 9.35 (1H, d,J=1.0 Hz).

EXAMPLE 167 (n=2, Aryl=4-bromophenyl)N-[2-(4-Bromo-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.06 (3H, d, J=6.4 Hz), 1.3-2.2 (2H, br),2.56-2.63 (2H, m), 2.95 (2H, t, J=5.7 Hz), 3.05 (1H, dq, J=8.0, 6.4 Hz),5.79 (1H, dd, J=15.9, 8.0 Hz), 6.22 (1H, d, J=15.9 Hz), 7.13 (2H, dm,J=8.5 Hz), 7.41 (2H, dm, J=8.5 Hz), 7.68 (1H, dd, J=8.3, 7.4 Hz), 8.19(1H, brd, J=8.3 Hz), 8.42-8.46 (2H, m), 8.69 (1H, d, J=6.1 Hz), 9.35(1H, d, J=1.0 Hz).

EXAMPLE 168 (n=2, Aryl=4-isopropylphenyl)N-[2-(4-isopropyl-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.05 (3H, d, J=6.6 Hz), 1.24 (6H, d, J=6.8 Hz),1.5-2.5 (2H, br), 2.56-2.63 (2H, m), 2.80-3.05 (3H, m), 5.74 (1H, dd,J=15.9, 8.0 Hz), 6.24 (1H, d, J=15.9 Hz), 7.16 (2H, d, J=8.6 Hz), 7.20(2H, d, J=8.6 Hz), 7.66 (1H, dd, J=8.3, 7.3 Hz), 8.17 (1H, brd, J=8.3Hz), 8.43 (1H, dd, J=7.3, 1.0 Hz), 8.44 (1H, d, J=6.1 Hz), 8.69 (1H, d,J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).

EXAMPLE 169 (n=2, Aryl=4-methoxyphenyl) N-[2-(4-Methoxy-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.05 (3H, d, J=6.4 Hz), 1.5-2.5 (2H, br),2.56-2.63 (2H, m), 2.96 (2H, t, J=5.6 Hz), 3.02 (1H, dq, J=8.0, 6.4 Hz),3.81 (3H, s), 5.64 (1H, dd, J=15.9, 8.0 Hz), 6.21 (1H, d, J=15.9 Hz),6.83 (2H, dm, J=8.8 Hz), 7.20 (2H, dm, J=8.8 Hz), 7.67 (1H, dd, J=8.3,7.3 Hz), 8.19 (1H, brd, J=8.3 Hz), 8.44 (1H, dd, J=7.3, 1.2 Hz), 8.44(1H, d, J=6.1 Hz), 8.69 (1H, d, J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).

EXAMPLE 170 (n=2, Aryl=4-hydroxyphenyl)N-[2-(4-hydroxy-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless crystals;

Melting point: 70°-73° C.;

¹ H-NMR (CDCl₃, δ ppm): 1.06 (3H, d, J=6.4 Hz), 2.61 (2H, brt, J=5.7Hz), 3.00 (2H, brt, J=5.7 Hz), 3.05 (1H, dq, J=8.0, 6.4 Hz), 3.3-3.5(3H, br), 5.61 (1H, dd, J=15.9, 8.0 Hz), 6.19 (1H, d, J=15.9 Hz), 6.75(2H, brd, J=8.5 Hz), 7.10 (2H, brd, J=8.5 Hz), 7.65 (1H, dt, J=8.3, 7.3Hz), 8.16 (1H, brd, J=8.3 Hz), 8.40-8.46 (2H, m), 8.59 (1H, d, J=6.1Hz), 9.32 (1H, d, J=1.0 Hz).

EXAMPLE 171 (n=3, Aryl=phenyl)N-[3-(α-Methylcinnamylamino)propyl]-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.27 (3H, d, J=6.6 Hz), 1.50-1.60 (2H, m),1.6-2.5 (2H, br), 2.60-2.67 (2H, m), 3.01-3.09 (2H, m), 3.24 (1H, dq,J=7.8, 6.6 Hz), 5.91 (1H, dd, J=15.9, 7.8 H.)z, 6.40 (1H, d, J=15.9 Hz),7.30 (5H, m), 7.68 (1H, dd, J=8.0, 7.3 Hz), 8.18 (1H, brd, J=8.0 Hz),8.43 (1H, dd, J=7.3, 1.2 Hz), 8.47 (1H, d, J=6.1 Hz), 8.67 (1H, d, J=6.1Hz), 9.36 (1H, d, J=1.0 Hz).

EXAMPLES 172 TO 188

In Examples 172 to 188, the following general reaction was used.##STR23##

EXAMPLE 172 (n=2, m=1, Aryl=4-chlorophenyl)

N-[2-(4-Chlorocinnamylamino)ethyl]-5-isoquinolinesulfonamide

2.01 g of N-(2-aminoethyl)-5-isoquinolinesulfonamide was dissolved in 30ml of methanol, to the solution was added 1.60 g ofp-chlorocinnamaldehyde, and the mixture was stirred for one hour at aroom temperature. After an addition of 350 mg of sodiumtetrahydrideborate in portions with ice cooling, the mixture was stirredfor 30 minutes. After an addition of ethyl acetate, the reaction mixturewas sequentially washed three times with water, and then twice with asaturated sodium chloride aqueous solution, and dried over magnesiumsulfate. The mixture was filtered and evaporated to remove the solventunder a reduced pressure. A residue was purified using a silica gelcolumn (silica gel 80 g, eluant: 5% methanol in chloroform), andresulting crystals were washed with benzene/hexane (1:1), to obtain 2.30g of the title compound as colorless crystals.

Melting point: 120°-123° C.;

¹ H-NMR (CDCl₃, δ ppm): 1.8-3.5 (2H, br), 2.64-2.70 (2H, m), 2.97-3.03(2H, m), 3.14 (2H, dd, J=6.1, 1.2 Hz), 6.00 (1H, dt, J=15.9, 6.1 Hz),6.32 (1H, d, J=15.9 Hz), 7.21 (2H, dd, J=8.8, 2.4 Hz), 7.28 (2H, dd,J=8.8, 2.4 Hz), 7.69 (1H, dd, J=8.3, 7.4 Hz), 8.19 (1H, dd, J=8.3, 1.0Hz), 8.42-8.47 (2H, m), 8.69 (1H, d, J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).

EXAMPLE 173 (n=2, m=1, Aryl=phenyl)N-(2-Cinnamylaminoethyl)-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.8-2.8 (2H, br), 2.64-2.69 (2H, m), 2.97-3.03(2H, m), 3.14 (1H, dd, J=6.3, 1.2 Hz), 6.02 (1H, dt, J=15.9, 6.3 Hz),6.46 (1H, dt, J=15.9, 1.2 Hz), 7.30 (5H, s), 7.68 (1H, dd, J=8.1, 7.3Hz), 8.18 (1H, dt, J=8.1, 1.0 Hz), 8.42-8.48 (2H, m), 8.70 (1H, d, J=6.1Hz), 9.34 (1H, d, J=1.0 Hz).

EXAMPLE 174 (n=2, m=1, Aryl=4-dimethylaminophenyl)N-[2-(4-Dimetylaminocinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 2.65 (2H, brs), 2.70 (2H, dd, J=6.1, 4.9 Hz),2.96 (6H, s), 3.02 (2H, dd, J=6.1, 4.9 Hz), 3.14 (2H, dd, J=6.6, 1.0Hz), 5.81 (1H, dt, J=15.9, 6.5 Hz), 6.27 (1H, brd, J=15.9 Hz), 6.66 (2H,brd, J=8.8 Hz), 7.20 (2H, brd, J=8.8 Hz), 7.68 (1H, dd, J=8.0, 7.5 Hz),8.18 (1H, dt, J=8.0, 1.0 Hz), 8.44 (1H, d, J=6.0 Hz and 1H, d, J=7.5Hz), 8.71 (1H, d, J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).

EXAMPLE 175 (n=2, m=1, Aryl=4 -fluorophenyl)N-[2-[4-Fluorocinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃ , δ ppm): 1.5-2.5 (2H, br), 2.63-2.69 (2H, m), 2.97-3.02(2H, m), 3.12 (2H, dd, J=6.1, 1.2 Hz), 5.94 (1H, dt, J=15.9, 6.1 Hz),6.33 (1H, d, J=15.9 Hz), 7.00 (2H, ddd, J=8.6, 8.6, 2.2 Hz), 7.27 (2H,ddd, J=8.6, 5.3, 2.2 Hz), 7.69 (1H, dd, J=8.2, 7.6 Hz), 8.19 (1H, brd,J=8.2 Hz), 8.42-8.48 (2H, m), 8.70 (1H, d, J=6.1 Hz), 9.35 (1H, d, J=1.0Hz).

EXAMPLE 176 (n=2, m=1, Aryl=4-bromophenyl)N-[2-(4-Bromophenylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless crystals;

Melting point: 124°-127° C.;

¹ H-NMR (CDCl₃, δ ppm): 2.0-3.5 (2H, br), 2.64-2.69 (2H, m), 2.97-3.03(2H, m), 3.13 (2H, dd, J=6.1, 1.0 Hz), 6.01 (1H, dt, J=15.9, 6.3 Hz),6.30 (1H, d, J=15.9 Hz), 7.14 (2H, dm, J=8.6 Hz), 7.41 (2H, dm, J=8.6Hz), 7.68 (1H, dd, J=8.3, 7.5 Hz), 8.18 (1H, brd, J=8.3 Hz), 8.43-8.47(2H, m}, 8.68 (1H, d, J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).

EXAMPLE 177 (n=2, m=1, Aryl=4-isopropylphenyl)N-[2-(4-Isopropylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

¹ H-NMR (CDCl₃, δ ppm): 1.24 (6H, d, J=7.1 Hz), 2.0-2.3 (2H, br),2.63-2.69 (1H, m), 2.87 (1H, q, J=7.1 Hz), 2.97-3.03 (2H, m), 3.13 (1H,dd, J=6.3, 1.2 Hz), 5.97 (1H, dt, J=15.9, 6.3 Hz), 6.33 (1H, brd, J=15.9Hz), 7.16 (2H, dm, J=8.3 Hz), 7.23 (2H, dm, J=8.3 Hz), 7.67 (1H, dd,J=8.3, 7.3 Hz), 8.17 (1H, d, J=8.3 Hz), 8.43-8.47 (2H, m), 8.69 (1H, d,J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).

EXAMPLE 178 (n=2, m=1, Aryl=4-methoxyphenyl)N-[2-(4-Methoxycinnamylamino)ethyl] -5-isoquinolinesulfonamide

Colorless crystals;

Melting point: 92°-95° C.;

¹ NMR (CDCl₃, δ ppm): 2.0-3.0 (2H, br), 2.63-2.69 (2H, m), 2.97-3.06(2H, m), 3.11 (2H, dd, J=6.3, 1.2 Hz), 3.81 (3H, s), 5.88 (1H, dt,J=15.9, 6.3 Hz), 6.30 (1H, d, J=15.9 Hz), 6.84 (2H, dm, J=8.8 Hz), 7.23(2H, dm, J=8.8 Hz), 7.68 (1H, dd, J=8.3, 7.5 Hz), 8.19 (1H, brd, J=8.3Hz), 8.42-8.47 (2H, m), 8.69 (1H, d, J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).

EXAMPLE 179 (n=2, m=1, Aryl=4-trifluoromethylphenyl).N-[2-(4-Trifluoromethylcinnamylamino)ethyl]-5isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.5-2.5 (2H, br), 2.66-2.72 (2H, m), 2.98-3.04(2H, m), 3.19 (2H, dd, J=6.1, 1.2 Hz), 6.14 (1H, dt, J=15.9, 6.1 Hz),6.41 (1H, d, J=15.9 Hz), 7.39 (2H, brd, J=8.3 Hz), 7.56 (2H, brd, J=8.3Hz), 7.69 (1H, dd, J=8.3, 7.3 Hz), 8.20 (1H, brd, J=8.3 Hz), 8.42-8.48(2H, m), 8.70 (1H, d, J=6.1 Hz), 9.35 (1H, d, J=1.0 Hz).

EXAMPLE 180 (n=2, m=2, Aryl=4-trifluoromethylphenyl)N-{2-[5-(4-Trifluoromethylphenyl)-2,4-pentadienylamino]ethyl}-5-isoquinolinesulfonamide

Light yellow amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.0-2.5 (2H, br), 2.61-2.67 (2H, m), 2.96-3.05(2H, m), 3.08 (2H, dd, J=6.3, 1.0 Hz), 5.69 (1H, dt, J=15.0, 6.3 Hz),6.19 (1H, dd, J=15.0, 10.0 Hz), 6.48 (1H, d, J=15.7 Hz), 6.75 (1H, dd,J=15.7, 10.0 Hz), 7.47 (2H, brd, J=8.3 Hz), 7.57 (2H, brd, J=8.3 Hz),7.72 (1H, dd, J=8.3, 7.3 Hz), 8.20 (1H, dt, J=8.3, 1.0 Hz), 8.43-8.48(2H, m), 8.72 (1H, d, J=6.1 Hz), 9.36 (1H, d, J=1.0 Hz).

EXAMPLE 181 (n=2, m=3, Aryl=4-trifluoromethylchenyl) N-{2-7-(4-Trifluoromethylphenyl)-2,4,6-heptatrienylamino]ethyl}-5-isoquinolinesulfonamide

Light yellow amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 2.0-3.5 (2H, br), 2.61-2.67 (2H, m), 2.95-3.01(2H, m), 3.07 (2H, dd, J=6.3, 1.0 Hz), 5.59 (1H, dt, J=14.6, 6.3 Hz),6.05-6.22 (1H, m), 6.29-6.34 (2H, m), 6.55 (1H, d, J=15.6 Hz), 6.81-6.93(1H, m), 7.47 (2H, brd, J=8.3 Hz), 7.55 (2H, brd, J=8.3 Hz), 7.71 (1H,dd, J=8.3, 7.3 Hz), 8.21 (1H, brd, J=8.3 Hz), 8.43-8.48 (2H, m), 8.72(1H, d, J=6.1 Hz), 9.37 (1H, d, J=1.0 Hz).

EXAMPLE 182 [n=2, m=1, Aryl=4-(2-methoxyethoxy)methoxyphenyl] N-{2-[4-(2-methoxyethoxy)methoxycinnamylamino]ethyl}-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.8-2.7 (2H, br), 2.63-2.69 (2H, m), 2.96-3.02(2H, m), 3.11 (2H, dd, J=6.4, 1.2 Hz), 3.37 (3H, s), 3.53-3.58 (2H, m),3.80-3.85 (2H, m), 5.27 (2H, s), 5.90 (1H, dt, J=15.9, 4 Hz), 6.30 (1H,d, J=15.9 Hz), 6.99 (2H, dm, J=8.8 Hz), 7.23 (2H, dm, J=8.8 Hz), 7.68(1H, dd, J=8.3, 7.3 Hz), 8.19 (1H, dt, J=8.3, 1.0 Hz), 8.42-8.47 (2H,m), 8.70 (1H, d, J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).

EXAMPLE 183 (n=2, m=1, Aryl= 4-hydroxyphenyl)N-[2-(4-Hydroxycinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless crystals;

Melting point: 156°-159° C.;

¹ H-NMR (DMSO-d₆, δ ppm): 2.44 (2H, brt, J=6.3 Hz), 2.88 (2H, brt, J=6.3Hz), 3.01 (2H, brd, J=6.1 Hz), 3.39 (3H, br), 5.83 (1H, dt, J=15.9, 6.1Hz), 6.20 (1H, d, J=15.9 Hz), 6.70 (2H, brd, J=8.3 Hz), 14 (2H, brd,J=8.3 Hz), 7.81 (1H, t, J=7.8 Hz), 8.34-8.46 (3H, m), 8.68 (1H, d, J=6.1Hz), 9.46 (1H, d, J=1.0 Hz).

EXAMPLE 184 (n=2, m=1, Aryl=1-naphthyl)N-{2-[3-(1-Naphthyl)-2-propenylamino]ethyl}-5-isoquinolinesulfonamide

Colorless crystals;

Melting point: 135°-138° C.;

¹ H-NMR (CDCl₃, δ ppm): 1.5-4.0 (2H, br), 2.68-2.73 (2H, m), 3.01-3.06(2H, m), 3.26 (1H, dd, J=3, 1.5 Hz, 6.00 (1H, dt, J=15.6, 6.3 Hz), 7.10(1H, d, J=15.6 Hz), 7.43-7.51 (4H, m), 7.61 (1H, dt, J=8.3, 7.3 Hz),7.78 (1H, dd, J=7.1, 2.7 Hz), 7.83-7.89 (1H, m), 7.97-8.02 (1H, m), 8.07(1H, brd, J=8.3 Hz), 8.44 (1H, dd, J=7.3, 1.0 Hz), 8.44 (1H, d, J=6.1Hz), 8.68 (1H, d, J=6.1 Hz), 9.27 (1H, d, J=1.0 Hz).

EXAMPLE 185 (n=2, m=1, Aryl=3,4,5-trimethoxyphenylN-[2-(3,4,5-Trimethoxycinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.5-2.6 (2H, br), 2.65-2.71 (2H, m), 2.97-3.03(2H, m), 3.15 (2H, dd, J=6.3, 1.2 Hz), 3.85 (3H, s), 3.88 (6H, s), 5.97(1H, dt, J=15.9, 6.3 Hz), 6.31 (1H, d, J=15.9 Hz), 6.55 (2H, s], 7.69(1H, dd, J=8.3, 7.5 Hz), 8.20 (1H, brd, J=8.3 Hz), 8.43 (1H, brd, J=6.1Hz), 8.46 (1H, dd, J=7.5, 1.2 Hz), 8.70 (1H, d, J=6.1 Hz), 9.35 (1H, d,J=1.0 Hz).

EXAMPLE 186 (n=2, m=1, Aryl=4-methoxycarbonylphenyl)N-[2-(4-Carbomethoxycinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless crystals;

Melting point 110°-113° C.

¹ H-NMR (CDCl₃, δ ppm): 1.2-2.0 (2H, br), 2.65-2.70 (2H, m), 2.97-3.02(2H, m), 3.17 (2H, dd, J=5.9, 1.2 Hz), 3.92 (3H, s), 6.15 (1H, dt,J=15.9, 5.9 Hz), 6.41 (1H, d, J=15.9 Hz), 7.36 (2H, dm, J=8.3 Hz), 7.69(1H, dd, J=8.3, 7.3 Hz), 7.98 (2H, dm, J=8.3 Hz), 8.19 (1H, brd, J=8.3Hz), 8.43 (1H, brd, J=6.1 Hz), 8.46 (1H, dd, J=7.3, 1.5 Hz), 8.71 (1H,d, J=6.1 Hz), 9.35 (1H, d, J=1.0 Hz).

EXAMPLE 187 (n=2, m=1, Aryl=4-carboxyphenyl)N-[2-(4-Carboxycinnamylamino)ethyl] -5-isoquinolinesulfonamide

Colorless crystals;

Melting points: 239° to 240° C. (decomposed);

¹ H-NMR (DMSO-d₆, δ ppm): 2.49 (2H, brt, J=6.3 Hz), 2.91 (2H, brt, J=6.3Hz), 3.13 (2H, brd, J=5.7 Hz), 3.0-4.0 (3H, br), 6.24 (1H, dt, J=16.1,5.7 Hz), 6.44 (1H, d, J=16.1 Hz), 7.44 (2H, brd, J=8.3 Hz), 7.82 (1H,dd, J=8.3, 7.3 Hz), 7.88 (2H, brd, J=8.3 Hz), 8.36 (1H, dd, J=7.3, 1.2Hz), 8.42 (1H, brd, J=8.3 Hz), 8.44 (1H, brd, J=6.1 Hz), 8.69 (1H, d,J=6.1 Hz), 9.46 (1H, d, J=1.0 Hz)

EXAMPLE 188 (n=3, m=1, Aryl=phenyl)N-(3-Cinnamylaminopropyl)-5-isoquinolinesulfonamide

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.5-2.2 (2H, br), 1.59 (2H, tt, J=5.6, 5.6 Hz),2.66 (2H, t, J=5.6 Hz), 3.06 (2H, t, J=5.6 Hz), 3.30 (2H, dd, J=6.1, 1.5Hz), 6.21 (1H, dt, J=15.9, 6.1 Hz), 6.52 (1H, d, J=15.9 Hz), 7.21-7.40(5H, m), 7.67 (1H, dd, J=8.3, 7.5 Hz), 8.18 (1H, d, J=8.3 Hz), 8.43 (1H,dd, J=7.5, 1.2 Hz), 8.44 (1H, d, J=6.1 Hz), 8.63 (1H, d, J=6.1 Hz), 9.35(1H, d, J=1.0 Hz).

EXAMPLE 189N-{2-[3-(4-Chlorophenyl)-2-propynylamino]ethyl}-5-isoquinolinesulfonamide(compound 189-I; N-{2-[Bis-(3-((4-chlorophenyl))-2-propynyl)amino]ethyl}-5-isoquinolinesulfonamide(compound 189-II);N-[3-(4-Chlorophenyl)-2-propynyl]-N-2-(p-chloropheny)-2-propynylamino]ethyl]-5-isoquinolinesulfonamide(compound 189-III) ##STR24##

1.90 g of N-(2-aminoethyl)-5-isoquinolinesulfonamide and 1.39 g of3-p-chlorophenyl-2-propynyl chloride were dissolved in 10 ml ofdimethylformamide, to the solution was added 1.38 g of potassiumcarbonate, and the mixture was stirred for 24 hours at a roomtemperature. The reaction mixture was poured to 100 ml of ethyl acetate,washed sequentially three times with water and the twice with asaturated sodium chloride aqueous solution, dried over magnesiumsulfate, filtered, and evaporated to remove the solvent under a reducedpressure. The resulting residue was separated and purified using asilica gel column (silica gel 100 g; eluant: 5% methanol/chloroform). Bycrystallizing from a mixture of ether-hexane, 855 mg of compound 189-Ias colorless crystals 220 mg of compound 189-II, and 214 mg of compound189-III in colorless amorphous form were obtained.

Compound 189-I

Colorless crystals;

Melting point; 120°-123° C.;

¹ H-NMR (CDCl₃, δ ppm): 1.30-1.80 (2H, br), 2.75-2.80 (2H, m), 3.00-3.05(2H, m), 3.39 (1H, s), 7.26 (4H, s), 7.69 (1H, dd, J=8.3, 7.3 Hz), 8.20(1H, dt, J=8.3, 1.0 Hz), 8.42 (1H, dt, J=6.1, 1.0 Hz), 8.46 (1H, dd,J=7.3, 1.2 Hz), 8.70 (1H, d, J=6.1 Hz), 9.36 (1H, d, J=1.0 Hz).

Compound 189-II

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 2.69-2.74 (2H, m), 3.01-3.09 (2H, m), 3.43 (4H,s), 5.48 (1H, t, J=5.0 Hz), 7.27 (4H, dm, J=9.0 Hz), 7.30 (4H, dm, J=9.0Hz), 7.68 (1H, dd, J=8.3, 7.3 Hz), 8.20 (1H, brd, J=8.3 Hz), 8.42 (1H,brd, J=6.1 Hz), 8.47 (1H, dd, J=7.3, 1.2 Hz), 8.66 (1H, d, J=6.1 Hz),9.35 (1H, d, J=1.0 Hz).

Compound 189-III

Colorless amorphous form;

¹ H-NMR (CDCl₃, δ ppm): 1.58 (1H, br), 3.02 (2H, t, J=6.0 Hz), 3.55 (2H,t, J=6.0 Hz) , 3.64 (2H, s), 4.50 (2H, s), 6.81 (2H, dm, J=8.8 Hz), 7.15(2H, dm, J=8.8 Hz), 7.27 (2H, dm, J=9.0 Hz), 7.31 (2H, dm, J=9.0 Hz),7.66 (1H, dd, J=8.3, 7.3 Hz), 8.13,(1H, brd, J=8.3 Hz), 8.48 (1H, dd,J=7.3, 1.2 Hz), 8.57 (1H, brd, J=6.1 Hz) , 8.69 (1H, d, J=6.1 Hz), 9.26(1H, d, J=1.0 Hz).

EXAMPLE 190N-2-(4-Chloro-N-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide##STR25##

1.50 g of the product of Example 172 was dissolved in 10 ml ofchloroform, to the solution was added 3 ml of methyl iodide at a roomtemperature, and the mixture was stirred for 40 minutes. Excess methyliodide was immediately evaporated off under a reduced pressure, andresulting residue was purified on a silica gel column (silica gel 50 g,eluant: 5% methanol in chloroform), to obtain 720 mg of the titlecompound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 1.4-2.1 (1H, br), 1.95 (3H, s), 2.37 (2H, t,J=5.5 Hz), 2.92-3.00 (3H, m), 5.97 (1H, dt, J=15.9, 6.6 Hz), 6.34 (1H,d, J=5.9 Hz), 7.25 (2H, dm, J=8.8 Hz), 7.28 (2H, dm, J=8.8 Hz), 7.68(1H, dd, J=8.3, 7.8 Hz), 8.19 (1H, brd, J=8.3 Hz), 8.44 (1H, brd, J=6.1Hz), 8.45 (1H, dd, J=7.8, 1.5 Hz), 8.69 (1H, d, J=6.1 Hz), 9.34 (1H, d,J=1.0 Hz).

EXAMPLE 191 1-(4-Chlorocinnamyl)-4-(5-isoquinolinesulfonyl)piperazine##STR26##

1.31 g of the product of Example 172 was dissolved in 3 ml ofdimethylformamide, to the solution were added 644 mg of1,2-dibromoethane and 1.13 g of anhydrous potassium carbonate at a roomtemperature, and the mixture was stirred for 24 hours. After adding 100ml of ethyl acetate, the ethyl acetate layer was sequentially washedwith water and a saturated sodium chloride aqueous solution twice ineach case, and dried over magnesium sulfate. The solution was filteredand evaporated under a reduced pressure, and resulting residue waspurified on a silica gel column (silica gel 50 g, eluant: 5% methanol inchloroform), to obtain 356 mg of the title compound in a colorlessamorphous form, while recovering the residual starting material.

¹ H-NMR (CDCl₃, δ ppm): 2.53 (4H, brt, J=4.9 Hz), 3.10 (2H, dd, J=6.6,1.2 Hz), 3.20 (4H, brt, J=4.9 Hz), 6.07 (1H, dt, J=15.9, 6.6 Hz), 6.43(1H, d, J=15.9 Hz), 7.24 (4H, s), 7.72 (1H, dd, J=8.1, 7.3 Hz), 8.22(1H, brd, J=8.1 Hz), 8.37 (1H, dd, J=7.3, 1.2 Hz), 8.55 (1H, brd, J=6.1Hz), 8.68 (1H, d, J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).

EXAMPLE 192N-Ethyl-N-[2-(4-chloro-N-ethylcinnamylamino)ethyl]-5-isoquinolinesulfonamide##STR27##

The procedure as described in Example 191 was repeated except that 1.31g of the product of Example 172 and 2.14 g of ethyl iodide asN-alkylating agent were used, to obtain 720 mg of the title compound ina colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 0.99 (3H, t, J=7.1 Hz), 1.05 (3H, t, J=7.1 Hz),2.53 (2H, q, J=7.1 Hz), 2.61 (2H, t, J=7.8 Hz), 3.19 (2H, dd, J=6.5, 1.2Hz), 3.33-3.43 (4H, m), 6.12 (1H, dt, J=15.9, 6.5 Hz), 6.32 (1H, d,J=15.9 Hz), 7.26 (4H, s), 7.62 (1H, dd, J=8.1, 7.3 Hz), 8.14 (1H, dd,J=8.1 Hz), 8.35 (1H, dd, J=7.3, 1.2 Hz), 8.42 (1H, brd, J=6.1 Hz), 8.66(1H, d, J=6.1 Hz), 9.31 (1H, d, J=1.0 Hz),

EXAMPLE 193N-[2-(4-Chloro-N-formylcinnamylamino)ethyl]-5-isoquinolinesulfonamide##STR28##

3 ml of formic acid and 3 ml of acetic anhydride were mixed and stirredat a room temperature, and to the mixture was added 1.41 g of theproduct of Example 172, and the mixture was stirred for one hour. Thereaction mixture was added to 50 ml of ethyl acetate and 30 ml ofsaturated sodium carbonate aqueous solution with ice, and the mixturewas stirred, and after foaming was terminated, the ethyl acetate layerwas sequentially washed twice with water and once with a saturatedsodium chloride aqueous solution, and dried over magnesium sulfate,filtered and evaporated under a reduced pressure. The resulting residuewas purified on a silica gel column (silica gel 60 g, eluant: 2%methanol in chloroform), to obtain 1.49 g of the title compound as amixture of two isomers (3:2) in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 3.07-3.16 (2H, m), 3.39-3.47 (2H, m), 3.90 (0.6x 2H, dd, J=6.3, 1.0 Hz), 4.03 (0.4 x 2H, dd, J=6.3, 1.0 Hz), 5.93(0.6H, dt, J=15.9, 6.3 Hz), 6.01 (0.4H, dt, J=15.9, 6.3 Hz), 6.40 (0.4H,d, J=15.9 Hz), 6.44 (0.6H, d, J=15.9 Hz), 7.20 (0.6×2H, d, J=8.8 Hz),7.21 (0.4×2H, d, J=8.8 Hz), 7.26 (0.6×2H, d, J=8.8 Hz), 7.27 (0.4×2H, d,J=8.8 Hz), 7.61 (0.6H, dd, J=8.0, 7.6 Hz), 7.64 (0.4H, dd, J=8.0, 7.6Hz), 8.05 (0.6H, s), 8.09 (0.4 H, s), 8.16 (0.6H, brd, J=8.0 Hz), 8.17(0.4H, brd, J=8.0 Hz), 8.33-8.42 (2H, m), 8.60 (0.4H, d, J=6.1 Hz), 8.65(0.6H, d, J=6.1 Hz), 9.33 (1H, d, J=1.0 Hz).

EXAMPLE 194N-{2-4-Chloro-N-(4-hydroxybenzyl)cinnamylamino)ethyl}-5-isoquinolinesulfonamide

0.2 g of the product of Example 172 and 0.13 g of p-hydroxybenzaldehydewere dissolved in 10 ml of methanol, to the solution were added 60 mg ofsodium cyanoborohydride and two drops of acetic acid, and the mixturewas stirred for 2 days at a room temperature. The reaction mixture wasconcentrated under a reduced pressure, and after adding a saturatedsodium chloride aqueous solution, extracted three times with 20 ml ofethyl acetate. The extracts were combined, washed with sodium chloride,dried over magnesium sulfate, filtered and concentrated under a reducedpressure. The resulting residue was purified on a silica gel column(silica gel 10 g, eluant: 2% methanol in chloroform), to obtain 150 mgof the title compound in a colorless amorphous form.

¹ H-NMR (CDCl₃, δ ppm): 2.50 (2H, brt), 2.90 (2H, brt), 3.10 (2H, d,J=6.6 Hz), 3.35 (2H, s), 6.06 (1H, dt, J=15.6, 6.6 Hz), 6.35 (1H, d,J=15.9 Hz), 6.75 (2H, d, J=8.5 Hz), 6.97 (2H, d, J=8.5 Hz), 7.30 (4H,s), 7.65 (1H, t, J=8.0 Hz), 8.15 (1H, d, J=8.0 Hz), 8.37-8.41 (2H, m),8.63 (1H, d, J=6.0 Hz), 9.32 (1H, s).

EXAMPLE 1952-Methyl-5-{[2-(4-chloro-N,N-dimethylcinnamylammonio)ethyl]aminosulfonyl}isoquinoliumdiiodide

83 mg of the product of Example 172 was dissolved in 2.0 ml ofdimethylformamide, to the solution was added 1.0 ml of methyl iodide,and the mixture was stirred for 4 hours at a room temperature. Excess ofmethyl iodide and dimethylformamide were evaporated off under a reducedpressure, and the resulting residue was crystallized from 5 ml of amixture of methanol/chloroform (1:5). Crude crystals thus obtained wasrecrystallized from 10 ml of a mixture of methanol/chloroform (1:5), toobtain 78 mg of the title compound as light yellow crystals.

Melting point: 199°-200° C.;

¹ H-NMR (DMSO-d₆, δ ppm): 3.09 (6H, s), 3.43 (4H, brs), 4.16 (2H, d,J=7.0 Hz), 4.53 (3H, s), 6.48 (1H, dt, J=15.9, 7.0 Hz), 6.89 (1H, d,J=15.9 Hz), 7.58 (2H, dm, J=9.4 Hz), 7.61 (2H, dm, J=9.4 Hz), 8.21 (1H,t, J=7.9 Hz), 8.72-8.78 (2H, m), 8.90-8.99 (3H, m), 10.22 (1H, brs).

EXAMPLE 1962-Methyl-5-{N-methyl-N-[2-(4-chloro-N,N-dimethylcinnamylammonio)ethyl]aminosulfonyl}isoquinoliumiodide

83 mg of the product of Example 172 was dissolved in 2.0 ml ofdimethylformamide, to the solution were added 1.0 ml of methyl iodideand 83 mg of anhydrous sodium carbonate, and the mixture was stirred for4 hours at a room temperature. Excess methyl iodide anddimethylformamide were evaporated off under a reduced pressure, andafter adding 10 ml of a mixture of methanol/chloroform (1:5) the mixturewas stirred, and then filtered to remove insoluble matter. The filtratewas concentrated under a reduced pressure, and to the concentrate wasadded 10 ml of a mixture of methanol/chloroform (1:5) to precipitate aninsoluble matter, which was then filtered off. This concentration andfiltration procedure was twice repeated, to obtain 145 mg of the titlecompound in yellow amorphous form.

¹ H-NMR (DMSO-d₆, δ ppm): 2.97 (3H, s), 3.15 (6H, s), 3.60-3.70 (2H, m),3.70-3.80 (2H, m), 4.21 (2H, d, J=7.3 Hz), 4.54 (3H, s), 6.54 (1H, dt,J=15.6, 7.3 Hz), 6.93 (1H, d, J=15.6 Hz), 7.48 (2H, brd, J=8.5 Hz), 7.63(2H, brd, J=8.5 Hz), 8.23 (1H, t, J=7.9 Hz), 8.75-8.85 (3H, m), 8.99(1H, d, J=7.1 Hz), 10.22 (1H, brs).

The isoquinoline compounds other than that of Example 174 can be treatedwith an excess amount of methyl iodide in dimethylformamide, asdescribed in this Example, to obtain corresponding compounds wherein thenitrogen atom on the isoquinoline ring has been methylated to aquaternary nitrogen atom.

EXAMPLE 197 N-[2-(4-Chlorocinnamylamino)ethyl]-5-isoquinolinesulfonamidedihydrochloride

2.00 g of the product of Example 172 was suspended in 20 ml of methanol,the suspension was made to a clear solution by adding 1 ml ofconcentrated hydrochloric acid, and stirred for 10 minutes with icecooling to form crystals. The crystals were collected by filtration, andrecrystallized from a mixture of 20 ml of methanol and 3 ml of water toobtain 1.65 g of the corresponding dihydrochloride as colorlesscrystals.

Melting point: 205°-208° C.;

¹ H-NMR (DMSO-d₆, δ ppm): 2.90-3.05 (2H, m), 3.10-3.20 (2H, m),3.65-3.75 (2H, m), 4.3-4.9 (br), 6.33 (1H, dt, J=16.1, 7.1 Hz), 6.76(1H, d, J=16.1 Hz), 7.45 (4H, s), 8.00 (1H, dd, J=8.3, 7.5 Hz), 8.54(1H, dd, J=7.5, 1.2 Hz), 8.64 (1H, brd, J=8.3 Hz), 8.71 (1H, brd, J=6.4Hz), 8.80 (1H, br), 8.82 (1H, d, J=6.4 Hz), 9.39 (1H, brs), 9.79 (1H,brs).

EXAMPLE 198 N-[2-(α-Methylcinnamylamino)ethyl]-5-isoquinolinesulfonamidedihydrochloride

The same procedure as described in Example 194 was repeated except thatthe product of Example 154 was used as a starting material, to obtainthe corresponding dihydrochloride as colorless crystals.

Melting point: 80°-85° C.;

¹ H-NMR (DMSO-d₆, δ ppm): 1.40 (3H, d, J=6.5 Hz), 2.89 (2H, m), 3.16(2H, brt, J=6.5 Hz), 3.91 (1H, m), 5.0-6.0 (br), 6.19 (1H, dd, J=16.1,7.5 Hz), 6.71 (1H, d, J=16.1 Hz), 7.39 (5H, m), 7.97 (1H, dd, J=8.0, 7.6Hz), 8.51-8.82 (5H, m), 9.44 (2H, br], 9.76 (1H, d, J=1.0 Hz)

EXAMPLE 199N-[2-(4-Chloro-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamidedihydrochloride

The same procedure as described in Example 194 was repeated except thatthe product of Example 153 was used as a starting material, to obtainthe corresponding dihydrochloride as a white hygroscopic powder.

¹ H-NMR (DMSO-d₆, δ ppm): 1.40 (3H, d, J=6.5 Hz), 2.85-3.96 (2H, m),3.10-3.20 (2H, m), 3.80-4.00 (1H, m), 5.1-6.1 (br), 6.23 (1H, dd,J=15.9, 8.5 Hz), 6.72 (1H, d, J=15.9 Hz), 7.44 (4H, s), 7.99 (1H, dd,J=8.2, 7.4 Hz), 8.54 (1H, dd, J=7.4, 1.2 Hz), 8.64 (1H, brd, J=8.2 Hz),8.72 (1H, brd, J=6.4 Hz), 8.80 (1H, br), 8.82 (1H, d, J=6.4 Hz), 9.48(2H, brs), 9.80 (1H, brs).

EXAMPLE 200 N-[2-(4-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamidedihydrochloride

The same procedure as described in Example 194 was repeated except thatthe product of Example 176 was used a starting material, to obtain thecorresponding dihydrochloride as colorless crystals.

Melting point: 195°-200° C.;

¹ H-NMR (DMSO-d₆, δ ppm): 2.90-3.10 (2H, brs), 3.2-3.3 (2H, m),3.65-3.75 (2H, brs), 6.35 (1H, dt, J=16.0, 7.1 Hz), 6.76 (1H, d, J=16.0Hz), 7.38 (2H, d, J=8.5 Hz), 7.57 (2H, d, J=8.5 Hz), 8.10 (1H, t, J=7.6Hz), 8.67 (1H, d, J=7.6 Hz), 8.78 (1H, d, J=7.6 Hz), 8.90 (1H, brs),9.05 (1H, brs), 10.0 (1H, s).

EXAMPLE 201 N-(2-Cinnamylaminoethyl)-5-isoquinolinesulfonamide.1/2fumarate

303 mg of the product of Example 173 was dissolved in 5 ml of ethylacetate, to the solution was added a solution of 89 ml of fumaric acidin 2 ml of methanol at a room temperature, and the mixture was stirredfor 30 minutes to from crystals, which was then collected by filtrationand washed with ethyl acetate to obtain 312 mg of the corresponding 1/2fumarate as colorless crystals.

Melting point: 153°-156° C.;

¹ H-NMR (DMSO-d₆, δ ppm): 2.69 (2H, brt, J=6.3 Hz), 3.00 (2H, brt, J=6.3Hz), 3.34 (2H, brd, J=6.1 Hz), 5.0-8.0 (3H, br), 6.16 (1H, dt, J=16.0,6.1 Hz), 6.51 (1H, d, J=16.0 Hz), 6.54 (1H, s), 7.23-7.3 (2H, m),7.34-7.40 (3H, m), 7.82 (1H, dd, J=8.1, 7.5 Hz), 8.36 (1H, dd, J=7.5,1.0 Hz), 8.42 (1H, brd, J=8.1 Hz), 8.44 (1H, brd, J=6.1 Hz), 8.69 (1H,d, J=6.1 Hz), 9.47 (1H, d, J=1.0 Hz).

EXAMPLE 202 N-[2-(α-Methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide1/2 fumarate

The same procedure as described in Example 198 was repeated except thatthe product of Example 154 was used as a starting material to obtain thecorresponding 1/2 fumarate as colorless crystals.

Melting point: 162°-167° C.;

¹ H-NMR (DMSO-d₆, δ ppm): 1.02 (3H, d, J=6.4 Hz), 2.49 (2H, brt, J=6.6Hz), 2.5-5.7 (3H, br), 2.93 (2H, brt, J=6.6 Hz), 3.17 (1H, dd, J=7.9,6.4 Hz), 5.91 (1H, dd, J=16.1, 7.9 Hz), 6.35 (1H, d, J=16.1 Hz), 6.55(1H, s), 7.32 (5H, m), 7.79 (1H, dd, J=8.0, 7.3 Hz), 8.34 (1H, dd,J=7.3, 1.2 Hz), 8.39 (1H, brd, J=8.0 Hz), 8.43 (1H, brd, J=6.1 Hz), 8.69(1H, d, J=6.1 Hz), 9.45 (1H, d, J=1.0 Hz).

EXAMPLE 203N-[2-(4-Chloro-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamideL-(+)-tartrate

6.60 g of the product of Example 153 was dissolved in 50 ml of ethylacetate, to the solution was added a solution of 2.38 g ofL-(+)-tartaric acid in methanol to form crystals, which was thencollected by filtration and washed with ethyl acetate to obtain thecorresponding L-(+)-tartrate as colorless crystals.

Melting point: 125°-130° C.;

¹ H-NMR (DMSO-d₆, δ ppm): 1.14 (3H, d, J=6.3 Hz), 2.64 (2H, brt, J=6.5Hz), 2.98 (2H, brt, J=6.5 Hz), 3.45 (1H, dd, J=8.0, 6.3 Hz), 3.5-4.7(6H, br), 4.13 (2H, s), 6.03 (1H, dd, J=15.9, 8.0 Hz), 6.49 (1H, d,J=15.9 Hz), 7.41 (4H, s), 7.81 (1H, dd, J=8.0, 7.3 Hz), 8.36 (1H, brd,J=8.0 Hz), 8.41 (1H, d, J=6.1 Hz), 8.42 (1H, brd, J=7.3 Hz), 8.69 (1H,d, J=6.1 Hz), 9.46 (1H, d, J=1.0 Hz).

EXAMPLE 204N-(2-Aminoethyl)-N-(2-cinnamylaminoethyl)-5-isoquinolinesulfonamidetrihydrochloride

To a solution of 1.10 g of the amorphous compound obtained in Example173, 1.18 g of triphenylphosphine and 0.73 g of2-(tert-butoxycarbonylamino)ethanol in 15 ml of tetrahydrofuran, wasadded dropwise a solution of 0.78 g of diethyl azodicarboxylate in 5 mlof tetrahydrofuran for 15 ml with ice cooling, and the mixture wasstirred for 4 hours at a room temperature. After again ice-cooling, tothe reaction mixture was added 0.39 g of triphenylphosphine, and addeddropwise a solution of 0.26 g of diethylazodicarboxylate in 3 ml oftetrahydrofuran, and the reaction mixture was stirred at a roomtemperature for one hour. The reaction mixture was concentrated under areduced pressure, and resulting residue was applied to a silica gelcolumn and eluted with chloroform/methanol (19:1), to obtain 0.99 g of alight orange amorphous product. The product was dissolved in 20 ml ofmethanol, to the solution was added 7.7 ml of 4N hydrochlonic acid inethyl acetate, and the mixture was stirred at a room temperature for 3hours. The reaction mixture was evaporated to remove the solvent under areduced pressure, and thereto was added ethyl acetate to form a solid.The solid was collected by filtration, washed with ethyl acetate andn-hexane, and dried under a reduced pressure to obtain 0.97 g of thetitle compound as a colorless hygroscopic powder.

NMR (D₂ O) δ ppm: 3.2-3.5 (4H, m), 3.7-4.0 (6H, m), 6.1-6.3 (1H, m),6.82 (1H, d, J=15.9 Hz), 7.44 (5H, s), 8.15 (1H, t, J=7.6 Hz), 8.1-8.3(3H, m), 9.09 (1H, d, J=7.0 Hz), 9.7 (1H, s).

EXAMPLE 205N-(4-Aminobutyl)-N-[2-(4-chlorocinnamylamino)ethyl]-5-isoquinolinesulfonamidetrihydrochlorides

To a solution of 0.4 g of the crystals obtained in Example 172. 0.226 gof 4-(tert-butoxycarbonylamino)butanol and 0.445 g of triphenylphosphinein 5 ml of tetrahydrofuran, was added a solution of 0.295 g of diethylazodicarboxylate in 2 ml of tetrahydrofuran with stirring under icecooling. The mixture was allowed to stand at room temperature, andevaporated under a reduced pressure to obtain a residue, which was thenapplied to a silica gel column and eluted with methanol/chloroform(2:98) to obtain 0.28 g of oil. To a solution of the oil in 1 ml ofmethanol, as added 4 N hydrochloric acid/ethyl acetate to form aprecipitate, which was then collected by filtration, washed with ethylacetate and dried to obtain 0.2 g of the title compound as a colorlesspowder.

NMR (D₂ O) δ ppm: 1.70 (4H, brs), 2.95 (2H, m), 3.30 (2H, m), 3.55 (2H,m), 3.77 (2H, m), 3.89 (2H, dd, J=7.3 Hz), 6.15 (1H, dt, J=15.8, 7.3Hz), 6.76 (1H, d, J=15.8 Hz), 7.35 (4H, s), 8.11 (1H, t, J=8.0 Hz),8.6-8.8 (2H, m), 8.98 (1H, d, J=7.0 Hz), 9.75 (1H, s).

EXAMPLE 206 N-[2-(4-Chloro-N-methylcinnamylamino)ethyl]-N-[2-(4-piperidyl)ethyl]-5-isoquinolinesulfoneamide

To a solution of 0.39 g of the amorphous compound obtained in Example190, 0.145 g of 4-piperidinethanol and 0.265 g of triphenylphosphine in5 ml of tetrahydrofuran, was added a solution of 0.245 g of diethylazodicarboxylate in 2 ml of tetrahydrofuran with ice cooling, and themixture was stirred for one hour at a room temperature and evaporated toremove the solvent under a reduced pressure. After an addition of 30 mlof ethyl acetate, the mixture was extracted three times with 5 ml of 1Nhydrochloric acid. The extract was alkalized with sodium bicarbonate andextracted three times with 10 ml of ethyl acetate. The organic layer wasdried over magnesium sulfate and evaporated to remove the solvent. Theresulting residue was applied to an alumina chromatographic column andeluted with 1% methanol in chloroform to obtain 180 mg of the titlecompound as colorless oil.

NMR (CDCl₃) δ ppm: 0.87-1.05 (2H, m), 1,30-1.45 (5H, m), 1.85 (1H, brs),2.21 (3H, s), 2.33 (2H, m), 2.51 (2H, t, J=7.6 Hz), 2.89 (2H, m), 3.08(2H, d, J=6.6 Hz), 3.30 (2H, t, J=7.8 Hz), 3.42 (2H, t, J=7.3 Hz), 6.09(1H, dt, J=15.8, 6.6 Hz), 6.41 (1H, d, J=15.8 Hz), 7.26 (4H, s), 7.65(1H, dd, J=8.0, 8.6 Hz), 8.15 (1H, d, J=8.0 Hz), 8.4 (1H, d, J=8.6 Hz),8.40 (1H, d, J=6.1 Hz), 8.67 (1H, d, J=6.1 Hz), 9.31 (1H, s).

The oil thus obtained was dissolved in 1 ml of methanol, and theretowere added 0.3 ml of 4N hydrochlonic acid in ethyl acetate and then 30ml of ether, to obtain the corresponding trihydrochloride as colorlesspowder.

EXAMPLE 207N-[2-(4-Chloro-N-methylcinnamylamino)ethyl]-N-[2-morpholinoethyl)-5-isoquinolinesulfonamidetrihydrochloride

To a solution of 1 g of the amorphous compound obtained in Example 190,0.377 g of 2-N-morpholinoethanol and 1.25 g of triphenylphosphine in 5ml of tetrahydrofuran, was added dropwise a solution of 0.835 g ofdiethyl azodicarboxylate in 2 ml of tetrahydrofuran with stirring underice cooling, and the mixture was stirred for 2 hours. After evaporatingoff the solvent under a reduced pressure, to the residue was added 20 mlof ethyl acetate, and the mixture was extracted three times with 10 mlof 1N hydrochloric acid. The extract was alkalized with sodiumbicarbonate and extracted three times with 10 ml of ethyl acetate. Theextract was dried over magnesium sulfate and evaporated under a reducedpressure to remove the solvent. The resulting residue was applied to asilica gel column and eluted with methanol/ethyl acetate (10:90) toobtain an oil.

NMR (CDCl₃) δ ppm: 2.18 (3H, s), 2.28-2.33 (4H, m), 2.4 (2.6 (4H, m),3.07 (2H, d, J=6.6 Hz), 3.4-3.6 (8H, m), 6.07 (1H, dt, J=15.9, 6.6 Hz),6.40 (1H, d, J=15.9 Hz), 7.26 (4H, s), 7.63 (1H, dd, J=8.0, 7.1 Hz),8.14 (1H, d, J=8.0 Hz), 8.42 (1H, d, J=7.1 Hz), 8.42 (1H, d, J=7.1 Hz),8.42 (1H, d, J=6.1 Hz), 8.67 (1H, d, J=6.1 Hz), 9.31 (1H, s).

The oil thus obtained was dissolved 4 ml of methanol, and was added in 2ml of 4N hydrochloric acid in ethyl acetate, and the solvent wasevaporated to remove the solvent under a reduced pressure, the resultingproduct was recrystallized from ethanol to obtain 0.67 g of the titlecompound as colorless crystals.

Melting point: 172°-176° C.;

NMR (D₂ O) δ ppm: 3.04 (3H, s), 3.2-3.6 (8H, m), 3.8-4.1 (10H, m), 6.18(1H, dt, J=15.9, 7.0 Hz), 6.76 (1H, d, J=15.9 Hz), 7.22 (4H, s), 8.09(1H, dd, J=7.6, 8.2 Hz), 8.52 (1H, d, J=7.6 Hz), 8.65-8.75 (2H, m), 8.87(1H, d, J=7.0 Hz), 9.74 (1H, s).

EXAMPLE 208N-[2-(4-Chloro-N-methylcinnamylamino)ethyl]-N-(2-piperidinoethyl)-5-isoquinolinesulfonamide

To a solution of 0.39 g of the amorphous compound obtained in Example190, 0.145 g of 1-piperidinethanol and 0.369 g of triphenylphosphine in5 ml of tetrahydrofuran, was added dropwise a solution of 0.245 g ofdiethyl azodicarboxylate in 2 ml of tetrahydrofuran with stirring underice cooling. The mixture was stirred for 2 hours and evaporated toremove the solvent under a reduced pressure, and resulting residuedissolved in 30 ml of ethyl acetate and extracted three times with 10 mlof 1N hydrochloric acid. The aqueous layer was alkallized with sodiumbicarbonate and extracted three times with 10 ml of ethyl acetate, andthe organic extract was dried over magnesium sulfate and evaporated toremove the solvent at a reduced pressure. The resulting residue wasapplied to a silica gel column and eluted with 2% methanol inchloroform, to obtain 0.37 g of the title compound as a colorless oil.

NMR (CDCl₃) δ ppm: 1.3-1.5 (6H, m), 2.20 (3H, s), 2.20-2.30 (4H, m),2.39 (2H, t, J=7.1 Hz), 2.55 (2H, t, J=7.1 Hz), 3.08 (2H, d, J=6.8 Hz),3.46 (4H, q, J=7.1 Hz), 6.09 (1H, dt, J=15.9, 6.8 Hz), 6.40 (1H, d,J=15.9 Hz), 7.25 (4H, s), 7.63 (1H, dd, J=7.3, 8.1 Hz), 8.14 (1H, d,J=8.1 Hz), 8.43 (1H, d, J=7.3 Hz), 8.43 (1H, d, J=6.1 Hz), 8.67 (1H, d,J=6.1 Hz), 9.31 (1H, s).

To a solution of above-obtained oil in 3 ml of methanol, was added 0.5ml of 4N hydrochloric acid in ethyl acetate, and the whole wasevaporated to remove the solvent under a reduced pressure. To theconcentrate was added ether to form powder, which was then collected byfiltration to obtain 0.35 g of the corresponding trihydrochloride as acolorless powder.

NMR (D₂ O) δ ppm: 1.3-2.0 (6H, m), 2.8-3.0 (2H, m), 3.05 (3H, s),3.3-3.6 (6H, m), 3.8-4.1 (6H, m), 6.25 (1H, dt, J=15.8, 8.0 Hz), 6.80(1H, d, J=15.8 Hz), 7.25 (4H, s), 8.13 (1H, t, J=8.0 Hz), 8.60 (1H, d,J=8.0 Hz), 8.68-8.78 (2H, m), 8.95 (1H, d, J=7.0 Hz), 9.70 (1H, s).

EXAMPLE 209N-[2-(4-Chloro-N-methylcinnamylamino)ethyl]-N-(2-dimethylaminoethyl)-5-isoquinolinesulfonamide

To a solution of 1.0 g of the amorphous compound obtained in Example190, 0.267 g of 2-dimethylamino ethanol and 0.982 g oftriphenylphosphine in 5 ml of tetrahydrofuran, was added dropwise asolution of 0.652 g of diethyl azodicarboxylate in 2 ml oftetrahydrofuran with stirring under ice cooling. After 2 hours, thereaction mixture was concentrated under a reduced pressure to removetetrahydrofuran, and resulting residue was dissolved in 10 ml of ethylacetate and extracted three times with 10 ml of 1N hydrochloric acid.The aqueous layer was alkalized with sodium bicarbonate and extractedthree times with 10 ml of ethyl acetate, and the organic layer was driedover magnesium sulfate and evaporated to removed the solvent under areduced pressure. The resulting residue was then applied to a silica gelcolumn and eluted with 3% methanol in chloroform, to obtain 0.77 g ofthe title compound as a colorless oil.

NMR (CDCl₃) , δ ppm: 2.11 (6H, s), 2.20 (3H, s), 2.38 (2H, t, J=7.3 Hz),2.54 (2H, t, J=7.3 Hz), 3.08 (2H, d, J=6.6 Hz), 3.38-3.50 (4H, m), 6.08(1H, dt, J=15.8, 6.6 Hz), 6.40 (1H, d, J=15.8 Hz), 7.26 (4H, s), 7.63(1H, dd, J=8.1, 7.5 Hz), 8.14 (1H, d, J=8.1 Hz), 8.40-8.45 (2H, m), 8.68(1H, d, J=6.1 Hz), 9.31 (1H, s).

To a solution of the oil thus obtained in 5 ml of methanol was added 1.4ml of 4N hydrochloric acid in ethyl acetate, and after evaporating offthe solvent under a reduced pressure, to the resulting concentrate wasadded ether to form powder, which was then collected by filtration anddried to obtain 0.7 g of the corresponding trihydrochloride as a powder.

NMR (D₂ O) δ ppm: 2.96 (6H, s), 3.03 (3H, s), 3.4-3.6 (4H, m), 3.9-4.1(6H, m), 6.17 (1H, dt, J=15.9, 7.0 Hz), 6.73 (1H, d, J=15.9 Hz), 7.19(4H, s), 8.01 (1H, t, J=8.0 Hz), 8.54 (1H, d, J=8.0 Hz), 8.70 (2H, m),8.91 (1H, d, J=8.0 Hz), 9.78 (1H, s).

EXAMPLE 210N-(2-Piperidinoethyl)-N-[2-(N-methylcinnamylamino)ethyl-5-isoquinolinesulfonamide

The amorphous product obtained in Example 173 was treated according tothe procedure described in Example 190, to obtainN-[2-(N-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide.

NMR (CDCl₃) δ ppm: 1.95 (3H, s), 2.37 (2H, t, J=5.7 Hz), 2.93-3.00 (4H,m), 6.00 (1H, dt, J=15.8, 6.6 Hz), 6.38 (1H, d, J=15.8 Hz), 7.31 (5H,s), 7.68 (1H, dd, J=8.3, 7.3 Hz), 8.18 (1H, d, J=8.3 Hz), 8.43-8.47 (2H,m), 8.69 (1H, d, J=6.1 Hz), 9.34 (1H, s).

To a solution of 0.476 g of the above compound, 0.193 g of1-piperidinethanol and 0.524 g of triphenylphosphine in 5 ml oftetrahydrofuran, was added a solution of 0.348 g of diethylazodicarboxylate in 2 ml of tetrahydrofuran with stirring under icecooling, and the mixture was allowed to stand for 3 hours and evaporatedto remove the solvent under a reduced pressure. To the concentrate wasadded 30 ml of ethyl acetate, and the mixture was extracted three timeswith 10 ml of 1N hydrochloric acid. The extract was alkalized withsodium bicarbonate and extracted three times with 10 ml of ethylacetate. The ethyl acetate solution was dried over magnesium sulfate andevaporated under a reduced pressure to remove the solvent. The resultingresidue was applied to a silica gel column and eluted with 5% methanolin chloroform, to obtain 0.44 g of the title compound as colorless oil.

NMR (CDCl₃) δ ppm: 1.3-1.5 (6H, m), 2.20 (3H, s), 2.20-2.30 (4H, m),2.41 (2H, t, J=6.8 Hz), 2.53 (2H, t, J=6.3 Hz), 3.09 (2H, d, J=6.6 Hz),3.4-3.55 (4H, m), 6.10 (1H, dt, J=15.8, 6.6 Hz), 6.45 (1H, d, J=15.8Hz), 7.2-7.4 (5H, m), 7.61 (1H, dd, J=8.0, 7.5 Hz), 8.11 (1H, d, J=8.0Hz), 8.4-8.5 (2H, m), 8.66 (1H, d, J=6.1 Hz), 9.29 (1H, s).

To the oil thus obtained in 5 ml of methanol was added 0.8 ml of 4Nhydrochloric acid in ethyl acetate, and the solution was evaporated toremove the solvent under a reduced pressure. A precipitate obtained byaddition of 50 ml of ether was collected by filtration and dried toobtain 0.4 g of the corresponding trihydrochloride as a colorlesspowder.

NMR (D₂ O) δ ppm: 1.6-2.0 (6H, m), 2.7-2.9 (2H, m), 3.04 (3H, s),3.4-3.6 (6H, m), 3.9-4.1 (6H, m), 6.25 (1H, dt, J=15.8, 8.0 Hz), 6.86(1H, d; J=15.8 Hz), 7.40 (5H, s), 8.14 (1H, t, J=8.0 Hz), 8.6-8.7 (3H,m), 9.0 (1H, d, J=7.0 Hz), 9.72 (1H, s).

EXAMPLE 211N-Anisyl-N-[2-(4-chlorocinnamylamino)ethyl]-5-isoquinolinesulfonamide

0.4 g of the crystals obtained in Example 172, 0.276 g of anisyl alcoholand 0.524 g of triphenylphosphine were dissolved in 10 ml oftetrahydrofuran, and to the solution was added dropwise a solution of0.404 g of diisopropyl azodicarboxylate in 2 ml of tetrahydrofuran withstirring under ice cooling. The reaction mixture was warmed to a roomtemperature and was allowed to stand overnight and then evaporated undera reduced pressure to remove the solvent. The resulting residue wasdissolved in 30 ml of ethyl acetate, and the mixture was extracted twicewith 30 ml of 1N hydrochloric acid. The extract was alkalized withsodium bicarbonate and extracted twice with 30 ml of ethyl acetate. Theethyl acetate solution was washed with water, dried over magnesiumsulfate and evaporated under a reduced pressure to remove the solvent.The resulting residue was applied to a silica gel column and eluted with1% methanol in chloroform, to obtain 0.22 g of the title compound as acolorless oil.

NMR (CDCl₃) δ ppm: 2.61 (2H, t, J=6.6 Hz), 3.14 (2H, d, J=6.1 Hz), 3.34(2H, t, J=6.6 Hz), 3.74 (3H, s), 4,43 (2H, s), 6.0 (1H, dt, J=15.9, 6.1Hz), 6.30 (1H, d, J=15.9 Hz), 6.75 (2H, d, J=8.8 Hz), 7.08 (2H, d, J=8.8Hz), 7.26 (4H, s), 7.66 (1H, dd, J=8.3, 7.3 Hz), 8.17 (1H, brd, J=8.3Hz), 8.39-8.49

(2H, m), 8.69 (1H, d, J=6.1 Hz), 9.3 (1H, s).

EXAMPLE 212N-[2-(4-Chlorocinnamylamino)ethyl]N-phenethyl-5-isoquinolinesulfonamide

The procedure described in Example 211 was repeated except that 0.146 gof phenethyl alcohol was used in place of anisyl alcohol, to obtain 0.37g of the title compound as a colorless oil.

NMR (CDCl₃) δ ppm: 1.4 (1H, brs), 2.75-2.90 (4H, m), 3.27 (2H, d, J=6.1Hz), 3,4-3.6 (4H, m), 6.10 (1H, dt, J=15.9, 6.1 Hz), 6.39 (1H, d, J=15.9Hz), 6.59-7.05 (2H, m), 7.1-7.2 (3H, m), 7.26 (4H, s), 7.65 (1H, dd,J=8.3, 7.6 Hz), 8.15 (1H, d, J=8.3 Hz), 8.38 (2H, t, J=6.1 Hz), 8.63(1H, d, J=6.1 Hz), 9.28 (1H, s).

EXAMPLE 213N-Benzyl-N-[2-(4-chlorocinnamylamino)ethyl]-5-isoquinolinesulfonamide

The procedure described in Example 211 was repeated except that 0.162 gof benzyl alcohol was used in place of anisyl alcohol, to obtain 0.3 gof the title compound as a colorless oil.

NMR (CDCl₃) δ ppm: 2.0 (1H, brs), 2.6 (2H, t, J=6.6 Hz), 3.15 (2H, d,J=6.1 Hz), 3.40 (2H, t, J=6.6 Hz), 4.50 (2H, s), 6.0 (1H, dt, J=15.8,6.1 Hz), 6.30 (1H, d, J=15.8 Hz), 7.15-7.25 (9H, m), 7.66 (1H, dd,J=8.0, 7.6 Hz), 8.16 (1H, d, J=8.0 Hz), 8.4-8.5 (2H, m), 8.70 (1H, d,J=6.1 Hz), 9.31 (1H, s).

EXAMPLE 214N-[2-(4-Chlorocinnamylamino)ethyl]-N-methyl-5-isoquinolinesulfonamide

The procedure described in Example 211 was repeated except that 48 mg ofmethanol was used in place of anisyl alcohol, to obtain 0.3 g of thetitle compound as a colorless oil.

NMR (CDCl₃) δ ppm: 1.5 (1H, brs), 2.86 (2H, t, J=6.2 Hz), 2.88 (3H, s),3.3-3.4 (4H, m), 6.15 (1H, dt, J=15.8, 6.1 Hz), 6.43 (1H, d, J=15.8 Hz),7.27 (4H, s), 7.69 (1H, dd, J=8.3, 7.3 Hz), 8.18 (1H, d, J=8.3 Hz), 8.38(1H, d, J=7.3 Hz), 8.50 (1H, d, J=6.3 Hz), 8.67 (1H, d, J=6.3 Hz), 9.31(1H, s).

REFERENCE EXAMPLE 45 N-(3,4-Dimethoxvphenyl)-5-isoquinolinesulfonamide

3.06 g of 3,4-dimethoxyaniline was dissolved in 30 ml of pyridine, tothe solution was added in small portions 5.28 g of5-isoquinolinesulfonyl chloride.HCl with stirring under ice cooling, andthe mixture was stirred for 30 minutes, and further stirred at a roomtemperature overnight. After evaporating off the pyridine under areduced pressure and additing 20 ml of water, the mixture was extractedtwice with 50 ml of chloroform/isopropanol (10:1). The extract was driedover magnesium sulfate and evaporated under a reduced pressure to removethe solvent. To the resulting residue was added 20 ml ofbenzene/chloroform (3:1), and the mixture was slightly warmed andcollected to obtain 5.64 g of the title compound as colorless crystals.

Melting point: 195°-197° C.;

NMR (CDCl₃) δ ppm: 3.67 (3H, s), 3.77 (3H, s), 6.3 (1H, dd, J=8.5, 2.7Hz), 6.5-6.6 (3H, complex), 7.61 (1H, t, J=8.3 Hz), 8.2 (1H, d, J=8.3Hz), 8.3 (1H, dd, J=1.3, 7.3 Hz), 8.4 (1H, d, J=6.1 Hz), 8.7 (1H, d,J=6.4 Hz), 9.36 (1H, d, J=1.3 Hz).

REFERENCE EXAMPLE 46N-(3,4-Dimethoxvphenyl)-N-(2-phthalimidethyl)-5-isoquinolinesulfonamide

500 mg of the crystals obtained in Reference Example 45 was dissolved in7 ml of dimethylformamide and 4 ml of tetrahydrofuran, to the solutionwas added 70 mg of 60% sodium hydride with stirring under ice cooling,and the mixture was stirred for 20 minutes, and after adding 406 mg ofbromoethylphthalimide, the whole was refluxed for 6 hours with stirring.After adding 10 ml of ice water, the reaction mixture was extracted with30 ml of ethyl acetate, and the extract was dried over magnesium sulfateand evaporated under a reduced pressure to remove the solvent. Theresulting residue was applied to a silica gel column and eluted withchloroform/methanol (100:1) to obtain 320 mg of the title compound ascolorless crystals.

Melting point: 197°-201° C.;

NMR (CDCl₃) δ ppm: 3.80 (3H, s), 3.88 (3H, s), 3.7-3.78 (2H, complex),3.75-4.0 (2H, complex), 6.67 (1H, s), 6.68 (1H, s), 6.73 (1H, s), 7.57(1H, t, J=7.57 Hz), 7.73 (4H, s), 8.0 (1H, dd, J=1.0, 8.3 Hz), 8.05 (1H,d, J=7.3 Hz), 8.24 (1H, dd, J=1.0, 7.57 Hz), 8.44 (1H, brd), 9.1 (1H,brs).

REFERENCE EXAMPLE 47N-(3,4-Dimethoxyphenyl)-N-(2-aminoethyl)-5-isoquinolinesulfonamide

517 mg of the crystals obtained in Reference Example 46 was dissolved in5 ml of methanol and 5 ml of chloroform, to the solution was added 60 mgof hydrozine hydrate, and the mixture was refluxed for 3 hours.Crystallized insoluble matter was filtered off, and the filtrate wasevaporated under a reduced pressure to remove the solvent. After anaddition of 10 ml of ethyl acetate, the whole was filtered to remove theinsoluble matter and then evaporated under a reduced pressure to yield420 mg of the title compound obtained as a slightly yellow oil.

NMR (CDCl₃) δ ppm: 2.76 (2H, t, J=6.1 Hz), 3.60 (3H, s), 3.75 (2H, t,J=6.1 Hz), 3.83 (3H, s), 6.48 (1H, s), 6.46 (1H, d, J=9.2 Hz), 6.63 (1H,d, J=9.2 Hz), 7.61 (1H, t, J=7.5 Hz), 8.18 (1H, d, J=8.0 Hz), 8.25 (1H,dd, J=1.3, 8.3 Hz), 8.5 (1H, d, J=6.1 Hz), 9.3 (1H, d, J=1.3 Hz).

EXAMPLE 215N-(3,4-Dimethoxvphenyl)-N-[2-(4-chlorocinnamylamino)ethyl]-5-isoquinolinesulfonamide

320 mg of the oil obtained in Reference Example 47 was dissolved in 6 mlof dimethylformamide, to the solution were added 200 mg of potassiumcarbonate and 150 mg of p-chlorocinnamyl chloride, and the mixture wasstirred overnight at a room temperature. After adding 20 ml of water thereaction mixture was extracted twice with 30 ml of chloroform. Theextract was washed with a saturated sodium chloride aqueous solution,dried over magnesium chloride and evaporated under a reduced pressure toremove the solvent. The resulting residue was applied to a silica gelcolumn and eluted with chloroform/methanol (100:1) to obtain 90 mg ofthe title compound as colorless crystals.

NMR (CDCl₃) δ ppm: 2.75 (2H, t, J=6.1 Hz), 3,36 (1H, d, J=6.1 Hz), 3.6(3H, s), 3.74 (2H, d, J=6.1 Hz), 3.82 (3H, s), 6.15 (1H, d, and dt,J=15.6, 6.1 Hz), 6.42 (1H, d, J=15.6 Hz), 6.5 (1H, s), 6.61 (1H, d,J=8.1 Hz), 6.48 (1H, d, J=6.1 Hz), 7.3 (4H, brs), 7.63 (1H, t, J=8.1Hz), 8.16 (1H, d, J=6.1 Hz), 8.17 (1H, d, J=8.1 Hz), 8.3 (1H, dd, J=1.0,6.1 Hz), 8.5 (1H, d, J=6.1 Hz), 9.3 (1H, d, J=1.0 Hz).

EXAMPLE 216N-{2-[Bis(4-chlorocinnamyl)amino]ethyl}-5-isoquinolinesulfonamide

In Example 215, prior to elution using chloroform/methanol, elution wascarried out using chloroform to obtain 100 mg of the title compound in acolorless amorphous form.

NMR (CDCl₃) δ ppm: 2.66 (2H, t, J=6.2 Hz), 3.25 (4H, d, J=6.2 Hz), 3.52(3H, s), 3.75 (2H, t, J=6.2 Hz), 3.71 (3H, s), 6.1 (2H, d and t, J=15.6,6.2 Hz), 6.3 (1H, d, J=5.6 Hz), 6.4 (1H, s), 6.4 (2H, d, J=15.6 Hz),6.45 (1H, d, J=5.6 Hz), 7.3 (8H, s), 7.51 (1H, t, J=8.1 Hz), 8.14 (1H,d, J=6.1 Hz), 8.16 (1H, d, J=8.1 Hz), 8.2 (1H, dd, J=1.0, 6.1 Hz), 8.45(1H, d, J=6.1 Hz), 9.3 (1H, d, J=1.0 Hz).

As described above, the following compounds were prepared.

EXAMPLE 217N-[2-4-methoxy-α-methylcinnamylamino)-ethyl]-5-isoquinolinesulfonamide.2HCl

Colorless amorphous form.

IR(KBr)cm⁻¹ : 3420, 3200-2300, 1720, 1605, 1345, 1280;

UMR(D₂ O) δ ppm: 1.59 (3H, d, J=6.71 Hz), 3.19 (2H, brt.), 3.38 (2H,brt), 4.01 (3H.s), 4.16 (1H, m), (1H, dd, J=15.9, 8.9 Hz), 6.83 (1H, d,J=15.9 Hz), 7.51 (2H, d, J=8.4 Hz), 7.94 (2H, d, J=8.4 Hz), 8.10 (1H,brt), 8.64 (1H, d, J=8.6 Hz), 8.76 (2H, brt), 8.98 (1H, d, J=7.0 Hz),9.72 (1H, s).

EXAMPLE 218 N-[2-(4-methoxycarbonyl-N,α-dimethyl-cinnamylamino)ethyl]-5isoquinolinesulfonamide.2HCl

Colorless amorphous form.

IR(KBr)cm⁻¹ =3420, 3150-2300, 1715, 1605, 1345, 1285;

NMR(D₂ O) δppm=1.59 (3H, α, J=6.4 Hz), 2.94 (3H, s), 3.44 (4H, brs),3.99 (3H, s), 4.31 (1H, m), 6.37 (1H, dd, J=16.2, 8.7 Hz), 6.89 (1H, d,J=16.2 Hz), 7.54 (2H, d, J=8.1 Hz), 8.08 (2H, d, J=8.1 Hz), 8.10 (1H,brt), 8.67 (1H, d, J=8.5 Hz), 8,75 (2H, brt), 8.96 (1H, d, J=7.0 Hz),9.74 (1H, s).

EXAMPLE 219N-[2-(4-methoxy-N,α-dimethylcinnamyl-amino)ethyl]-5-isoquinolinesulfonamide

Colorless oil.

NMR (CDCl₃)δppm: 1.07 (3H, d, J=6.6 Hz), 1.85 (3H, s), 2.3-2.5 (2H, m),2.91 (2H, t, J=6.0 Hz), 2.95-3.10 (1H, m), 3.80 (3H, s), 5.86 (1H, dd,J=6.0 Hz), 2.95-3.10 (1H, m), 3.80 (3H, s), 5.86 ((1H, dd, J=16.1, 7.3Hz), 6.24 (1H, d, J=16.1 Hz), 6.84 (2H, d, J=8.8 Hz), 7.24 (2H, d, J=8.8Hz), 7.68 (1H, dd, J=7.3, 8.0 Hz), 8.20 (1H, α, J=8.0 Hz), 8.4-8.5 (2H,m), 8.66 (1H, d, J=6.1 Hz), 9.34 (1H, s).

EXAMPLE 220 N-(2-methylaminoethyl)-N-[2-(4-chloroN-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless oil.

NMR (CDO₃)δppm: 1.9-2.2 (1H, br), 2.23 (3H, s), 2.35 (3H, s), 2.59 (2H,t. J=6.6 Hz), 2.80 (2H, t, J=6.1 Hz), 3.12 (2H, α, J=6.6 Hz), 3.4-5.5(4H, m), 6.10 ((1H, dt, J=15.9, 6.6 Hz), 6.44 ((1H, d, J=15.9 Hz), 7.26(4H, s), 7.66 (1H, t, J=15.9, 6.6 Hz), 6.44 (1H, d, J=15.9 Hz), 7.26(4H, s), 7.66 (1H, t, J=7.8 Hz), 8.17 (1H, d, J=7.8 Hz), 8.40 (1H, d,J=7.8 Hz), 8.46 (1H, d, J=6.1 Hz), 8.67 (1H, d, J=6.1 Hz), 9.32 (1H, s).

EXAMPLE 221N-(2-methylaminoethyl)-N-[2-(4-chloro-N-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide.3HCl

Colorless amorphous form.

NMR(D₂ O)δppm: 2.80 (3H, s), 3.05 (3H, s), 3.4-3.6 (4H, m), 3.9-4.1 (6H,m), 6.17 (1H, d.t, J=15.9, 7.2 Hz), 6.74 (1H, d, J=15.9 Hz), 7.18 (4H,s), 8.10 (1H, t, J=7.9 Hz), 8.53 (1H, d, J=7.9 Hz), 8.6-8.8 (2H, m),8.93 (1H, d, J=7.0 Hz), 9.77 (1H, s).

EXAMPLE 222N-(2-hydroxyethyl)-N-[2-(4-methoxy-N,α-dimethylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form.

NMR(CDCl₃)δppm: 1.29 (3H, d, J=6.6 Hz), 2.30 (3H, s), 2.7-3.0 (2H, m),3.2-3.4(5H, m), 3.80 (3H, s), 3.8-3.9 (2H, m), 6.04 (1H, dd, J=16.1, 7.8Hz), 6.40 (1H, d, J=16.1 Hz), 6.86 (2H, d, J=16.1, 7.8 Hz), 6.40 (1H, d,J=16.1 Hz), 6.86 (2H, d, J=8.7 Hz), 7.32 (2H, d, J=8.7 Hz), 7.32 (2H, d,J=8.7 Hz), 7.68 (1H, dd, J=8.0, 7.3 Hz), 8.19 (1H, d, J=8.0 Hz), 8.26(1h, d, J=7.3 Hz), 8.58 (1H, d, J=6.1 Hz), 8.68 (1H, d, J=6.1 Hz), 8.68(1H, d, J=6.1 Hz), 9.33 (1H, s).

EXAMPLE 223N-[2-(methoxy)ethyl]-N-[2-(N-methyl-4-methoxy-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless oil

NMR(CDCl₃)δppm: 1.12 (3H, d. J=6.6 Hz), 2.18 (3H, s), 2.4-2.65 (2H, m),3.1 (3H, s), 3.10-3.20 (1H, m), 3.35-3.60 (6H, m), 3.81 (3H, s), 5.93(1H, d,d, J=16.1, 7.3 Hz), 6.31 (1H, d, J=16.1 Hz), 6.85 (2H, d, J=8.7Hz), 7.62 (1H, dd, J=7.6, 8.1 Hz), 8.13 (1H, d, J=8.1 Hz), 8.35-8.45(2H, m) 8.67 (1H, d, J=6.1 Hz), 9.30 (1H, s).

EXAMPLE 224N-[2-(4-chlorocinnamylamino)ethyl]-N-(2-dimethylaminoethyl-5-isoquinolinesulfornamide.3HCl

Colorless amorphous form.

IR(KBr)cm⁻¹ : 3420, 2700, 1340, 1150, 840, 590.

NMR(D₂ O)δppm: 2.99 (6H, s), 3.33 (2H, t, J=6.8 Hz), 3.55 (2H, t, J=6.8Hz), 3.8-4.0 (6H, m), 6.18 (1H, dt, J=16.2, 6.7 Hz), 6.76 (1H, d, J=16.2Hz), 7.32 (4H, s), 8.12 (1H, t, J=8.0 Hz), 8.6-8.8(3H, m), 8.97 (1H, d,J=7.0 Hz), 9.74 (1H, s).

EXAMPLE 225N-[2-(4-chlorocinnamylamino)ethyl]-N-(2-methylaminoethyl)-5-isoquinolinesulfonamide

Colorless amorphous form.

NMR(D₂ O)δppm: 3.26 (2H, brt), 3.92 (4H, brt), 5.04 (2H, s), 6.1-6.3(1H, m), 6.77 (1H, d, J=15.6 Hz), 7.38 (4H, s), 7.68 (1H, t, J=6.7 Hz),8.0-8.3 (2H, m), 8.57 (1H, d, J=5.8 Hz), 8.7-8.9 (3H, m), 9.02 (1H, d,J=7.3 Hz), 9.80 (1H, s).

EXAMPLE 226N-2-(4-chlorocinnamylamino)ethyl]-N-(2-pyridiylmethyl)-5-isoquinolinesulfonamide.3HCl

Pale yellow amorphous form.

IR(KBr)cm⁻¹ : 3420, 2800, 1350, 1150, 590;

NMR(D₂ O)δppm: 3.12 (2H, brt), 3.8-4.0 (4H, m), 4.96 (2H, s), 6.0-6.2(1H, m), 6.70 (1H, d, J=15.7 Hz), 7.37 (4H, brq), 7.93 (1H, t, J=6.3Hz), 8.16 (2H, brt), 8.54 (1H, d, J=5.8 Hz), 8.61 (1H, d, J=8.5 Hz),8.7-8.8 (2H, m), 8.83 (1H, s), 9.01 (1H, d, J=6.7 Hz), 9.76 (1H, s).

EXAMPLE 227N-[2-(4-chlorocinnamylamino)ethyl]-N-(3-pyridylmethyl)-5-isoquinolinesulfonamide.3HCl

Pale yellow amorphous form.

IR(KBr)cm⁻¹ : 3420, 2800, 1350, 1150, 590;

NMR(D₂ O)δppm: 3.12 (2H, brt), 3.8-4.0 (4H, m), 4.96 (2H, s), 6.0-6.2(1H, m), 6.70 (1H, d, J=15.7 Hz), 7.37 (4H, brq), 7.93 (1H, t, J=6.3Hz), 8.16 (2H, brt), 8.54 (1H, d, J=5.8 Hz), 8.61 (1H, d, J=6.7 Hz),9.76 (1H, s).

EXAMPLE 228 N-[2-(3,4-dimethoxy-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl

Yellow amorphous form.

HMR(D₂ O)δppm: 1.56 (3H, d, J=6.7 Hz), 3.1-3.2 (2H, m), 3.35-3.45 (2H,m), 3.84 (3H, s), 3.91 (3H, s), 4.0-4.5 (1H, m), 6.0 (1H, dd, J=15.6,9.0 Hz), 6.64 (1H, d, J=15.6 Hz), 6.92 (3H, s), 8.07 (1H, t, J=8.0 Hz),8.60 (1H, d, J=8.0 Hz), 8.73 (1H, d, J=8.0 Hz), 8.73 (1H, d, J=6.7 Hz),8.95 (1H, d, J=6.7 Hz), 9.68 (1H, s).

EXAMPLE 229 N-[2-(α-methyl-3, 4,5,trimethoxycinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl

NMR (D₂ O) δppm: 1.65 (3H, d, J=6.4 Hz), 3.2-3.5 (4H, m), 3.84 (3H, s),3.91 (6H, s), 4.1-4.3 (1H, m), 6.13 (1H, dd, J=14.1, 8.8 Hz), 6.70 (1H,d, J=14.1 Hz), 6.67 (2H, s), 8.16 (1H, t, J=8.0 Hz), 8.17 (1H, d, J=8.0Hz), 8.75-8.85 (2H, m), 9.02 (1H, t, J=8.0 Hz), 8.17 (1H, d, J=8.0 Hz),8.75-8.85 (2H, m), 9.02 (1H, d, J=7.0 Hz), 9.80 (1H, s).

EXAMPLE 230 N-[2-dimethylaminoethyl)-N-[2-(N-methyl-3, 4,5-trimethoxycinnamylamino)ethyl]-5-isonolinesulfonamide

Colorless oil.

NMR(CDCL₃)δppm: 2.12 (6H, s), 2.22 (3H, s), 2.39 (2H, t, J=6.8 Hz), 3.10(2H, d, J=6.6 Hz), 3.4-3.5 (4H, m), 3.84 (3H, s), 3.87 (6H, s), 6.06(1H, dt, J=16, 6.6 Hz), 6.40 (1H, d, J=16 Hz), 6.61 (2H, s), 7.64 (1H,t, J=7.4 Hz), 8.15 (1H, d, J=7.4 Hz), 8.44 (2H, m), 8.68 (1H, d, J=6.1Hz), 9.32 (1H, s).

EXAMPLE 231 N-(2-dimethylaminoethyl)-N-[2-(N-methyl-3, 4,5-trimethoxycinnamylamino)ethyl]-5-isoquinolinesulfonamide.3HCl

Yellow amorphous form.

NMR (D₂ O)δppm: 3.00 (6H, s), 3.08 (3H, s), 3.80 (3H, s), 3.82 (6H, s),3.5-4.1 (10H, m), 6.1 (1H, m), 651 (2H, s), 6.68 (1H, d, J=16 Hz), 8.0(1H, t, J=16 Hz), 8.5 (2H, m), 8.7 (2H, m), 9.55 (1H, s).

EXAMPLE 232 N-[2-(4-chlorocinnamylamino)ethyl]-N-(3, 4,5-trimethoxybenzyl)-5-isoquinolinesulfonamide.2HCl

Colorless amorphous form.

IR (KBr)cm⁻¹ =3420, 2920, 1330, 1130, 590;

NMR (DMSO-d₆)δppm: 2.99 (2H, brs), 3.55 (6H, s), 3.56 (3H, s), 3.68 (4H,brs), 4.47 (2H, s), 6.2-6.4 (1H, m), 6.76 (1H, d, J=15.9 Hz), 7.45 (4H,s), 7.95 (1H, t, J=7.9 Hz), 8.54 (1H, d, J=7.6 Hz), 8.6-8.7 (2H, m),8.78 (1H, d, J=6.3 Hz), 9.48 (2H, brs), 9.73 (1H, s).

EXAMPLE 233N-cyanomethyl-N-[2-(4-methyoxycorbonyl-N-α-dimethylcinnamylaminolethyl]-5-isoquinolinesulfonamide

Colorless oil.

IR (KBr)cm⁻¹ : =2250, 1718, 1280;

NMR (CDCl₃)δppm =1.16 (3H, d, J=6.6 Hz), 2.23 (3H, s), 2.65-2.8 (2H, m),3.35 (1H, m), 3.43 (2H, t, J=5.6 Hz), 3.91 (3H, s), 4.63 (2H, s), 6.23(1H, dd, J=15.9, 7.1 Hz), 6.46 (1H, d, J=15.9 Hz), 7.39 (2H, d, J=8.3Hz), 7.73 (1H, t, J=8.3 Hz), 7.98 (2H, d, J- 8.3 Hz), 8.25 (1H, d, J -8.3 Hz), 8.4-8.5 (2H, m), 8.70 (1H, d, J=6.1 Hz), 9.36 (1H, s).

EXAMPLE 234N-cyanomethyl-N-[2-(4-methoxycarbonyl-N,α-dimethylcinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl

Colorless amorphous form

IRC (KBr)cm⁻¹ : =1718, 1280;

NMR (CDCl₃)δppm: 1.14 (3H, d, J=6.6 Hz), 2.10 (6H, s), 2,21 (3H, s),2.37 (2H, t, J=7.3 Hz), 2.45-2.65 (2H, m), 3.22 (1H, m), 3.35-3.50 (4H,m), 3.91 (3H, s), 6.21 (1H, dd, J=1.59, 6.8 Hz), 6.42 (1H, d, J=15.9Hz), 8.15 (1H, t, J=7.7 Hz), 8.7-8.85 (3H, m), 8.99 (1H, d, J=7.0 Hz),9.76 (1H, s).

EXAMPLE 235N-(2-dimethylaminoethyl)-N-[2-(4-methoxycarbonyl-N,α-dimethylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless oil.

IRC (KBr)cm⁻¹ : 1718, 1280;

NMR (CDCl₃)δppm: 1.14 (3H, d, J=6.6 Hz), 2.10 (6H, s), 2.21 (3H, s),2.37 (2H, t, J=7.3 Hz), 2.45-2.65 (2h, m), 3.22 (1H, m), 3.35-3.50 (4H,m), 3.91 (3H, s), 6.21 (1H, dd, J=15.9, 6.8 Hz), 6.42 (1H, d, J=15.9Hz), 7.38 (2H, d, J=8.3 Hz), 7.63 (1H, t, J=7.9 Hz), 7.98 (2H, d, J=8.3Hz), 8.14 (1H, d, J=7.9 Hz), 8.4-8.5 (2H, m), 8.67 (1H, d, J=6.4 Hz),9.31 (1H, s).

EXAMPLE 236 N-(2-dimethylaminoethyl)-N-[2-(4-methoxycarbonyl-N,α-dimethylcinnamylamino)-ethyl]-5-isoquinolinesulfonamide.3HCl

Colorless amorphous.

NMR (D₂ O) δppm: 1.53 (3H, d, J=6.7 Hz), 2.95 (9H, s), 3.3-3.6 (4H, m],3.9-4.0 (4H, m), 4.0 (3H, 4.25 (1H, m), 6.30 (1H, m), 6.75 (1H, d,J=16.0 Hz), 7.37 (2H, brs), 7.81 (2H, brs), 8.04 (1H, t, J=8.1 Hz), 8.55(2H, m), 8.65 (1H, d, J=7.0 Hz), 9.60 (1H, s).

EXAMPLE 237 N-(2-morpholinoethyl)-N-[2-(4-methoxycorbonyl-N,α-dimethylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless oil.

IR (KBr)cm⁻¹ : 1720, 1280;

NMR (CDCl₃)δppm: 1.15 (3H, d, J=6.4 Hz), 2.21 (3H, s), 2.25-2.7 (2H, m),3.1-3.3 (1H, m), 3.4-3.6 (8H, m), 3.91 (3H, s), 6.20 (1H, dd, J=16.1,7.3 Hz), 6.42 (1H, d, J=16.1 Hz), 7.38 (2H, d, J=8.3 Hz), 7.63 (1H, t,J=7.8 Hz), 8.42 (1H, d, J=7.8 Hz), 8.42 (1H, d, J=7.1 Hz), 8.67 (1H, d,J=7.1 Hz), 9.32 (1H, s).

EXAMPLE 238N-(2-morpholinoethyl)-N-[2-(4-methoxy-carbonyl-N,α-dimethylcinnamylamino)ethyl-5-isoquino-linesulfonamide.3HCl

Colorless amorphous form

NMR (D₂ O)δppm: 1.55 (3H, d, J=6.8 Hz), 3.00 (3H, s), 3.2-3.7 (8H, m),3.8-4.1 (8H, m), 4.0 (3H, s), 4.24 (1H, m), 6.35 (1H, m), 6.76 (1H, d,J=16 Hz), 7.40 (2H, brs), 7.82 (2H, brs), 8.06 (1H, t, J=7.5 Hz),8.5-8.75 (3H, m), 8.80 (1H, d, J=7.0 Hz), 9.63 (1H, s).

EXAMPLE 239 N-(2-aminoethyl)-N-[2-(4-methoxy-carbonyl-N,α-dimethylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless oil.

IR (KBr)cm⁻¹ : 1718, 1280;

NMR (CDCl₃)δppm: 1.13 (3H, d, J=6.6 Hz), 2.19 (3H, s), 2.6 (2H, m), 2.86(2H, brs), 3.22 (1H, m), 3.37 (4H, t, J=6.9 Hz), 3.91 (3H, s), 6.20 (1H,dd, J=16.0, 6.9 Hz), 6.42 (1H, d, J=16.0 Hz), 7.39 (2H, d, J=8.3 Hz),8.14 (1H, d, J=8.1 Hz), 8.38 (1H, d, J=8.1 Hz), 8.45 (1H, d, J=6.1 Hz),8.68 (1H, d, J=6.1 Hz), 9.31 (1H, s).

EXAMPLE 240N-(2-aminoethyl)-N-[2-(4-methoxycarbonyl-N,α-dimethylcinnamylamino)ethyl]-5-isoquinolinesulfonamide.3HCl

Colorless amorphous form.

NMR(D₂ O)δppm: 1.53 (3H, d, J=6.4 Hz), 2.96 (3H, s), 3.3-3.5 (4H, m),3.8-4.0 (4H, m), 4.0 (3H, s), 4.2 (1H, m), 6.3 (1H, m), 6.76 (1H, d,J=15.9 Hz), 7.35 (2H, d, J=8.0 Hz), 7.78 (2H, brs), 803 (1H, t, J=7.9Hz), 8.6 (2H, m), 8.66 (1H, d, J=6.7 Hz), 8.85 (1H, d, J=6.7 Hz), 9.58(1H, s).

EXAMPLE 241N-[2-(4-chloro-N-methylcinnamylamino)ethyl]-N-methoxycarbonylmethyl-5-isoquinoline-sulfonamide.2HCl

Yellow amorphous form.

IR (KBr)cm⁻¹ : 3420, 2650, 1750, 1350, 1150, 840, 590;

NMR (D₂ O)δppm: 3.05 (3H, s), 3.51 (2H, brs), 3.61 (3H, s), 3.89 (2H,brs), 4.06 (2H, d, J=7.3 Hz), 4.45 s), 6.2-6.4 (1H, m), 6.85 (1H, d,J=15.6 Hz), 7.34 (4H, brq), 8.12 (1H, t, J=8.0 Hz), 8.6-8.8 (3H, m),8.95 (1H, d, J=7.0 Hz), 9.79 (1H, s).

EXAMPLE 242N-carboxymethyl-N-(2-(4-chloro-N-methylcinamylamino)ethyl]-5-isoquinolinesulfornamide

Pale brown amorphous form.

IR (KBr)cm⁻¹ : 3420, 1620, 1330, 1140, 590:

NMR(DMSO-d₆)δppm: 2.43(3H, s), 2.89 (2H, brt), 3.3-3.6 (4H, m), 3.91(2H, s), 6.2-6.4(1H, m), 6.67 (1H, d, J=15.8 Hz), 7.45 (4H, brq), 7.85(1H, t, J=8.0), 8.3-8.5 (3H, m), 8.71 (1H, d, J=6.2 Hz), 9.49 (1H, s).

EXAMPLE 243N-[2-(N-carboxymethyl-4-chloracinnamylamino)ethyl]-N-methyl-5-isoquinoliesulfonamide

Pale yellow amorphous form.

IR (KBr)cm⁻¹ : 3400, 1630, 1320, 1140, 590;

NMR (DMSO-d₆)δppm: 2.75 (2H, brt), 2.79 (3H, s), 3.2-3.4(6H, m), 6.1-6.3(1H, m), 6.50(1H, d, J=16.2 Hz), 7.39 (4H, brq), 7.83 (1H, t, J=7.8 Hz),8.3-8.5 (3H, m), 8.68 (1H, d, J=6.1 Hz), 9.48 (1H, s).

EXAMPLE 244N-[2-(4-chloro-N-methylcinnamylamino)ethyl]-N-methyl-5-isoquinolinesulfonamide.2HCl

Pale brown amorphous form.

IR (KBr)cm⁻¹ : 3420, 2670, 1350, 1140, 830, 590;

NMR(D₂ O)δppm: 3.00 (3H, s), 3.04 (3H, s), 3.51 (2H, brs), 3.66 (2H,brs), 4.10 (2H, brd), 6.2-6.4 (1H, m), 6.90 (1H, d, J=15.9 Hz), 7.39(4H, brq), 8.15 (1H, t, J=8.0 Hz), 8.6-8.8 (3H, m), 9.08 (1H, d, J=6.3Hz), 9.80 (1H, s).

EXAMPLE 245N-carbamoyl-N-[2-(4-chloro-N-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl

Colorless amorphous.

IR (KBr)cm⁻¹ : 3420, 2670, 1680, 1350, 1150, 840, 590;

NMR (D₂ O)δppm: 3.04 (3H, s), 3.4-3.7 (2H, m), 3.89 (2H, brt), 4.06 (2H,brt), 4.29 (2H, s), 6.2-6.4 (1H, m), 6.86 (1H, d, J=7.0 Hz), 9.80 (1H,s).

EXAMPLE 246N-[2-(4-chlorocinnamylamino)ethyl]-N-[(5-methyl-4-imidazolyl)methyl]-5-isoquinolinesulfonamide.HCl

Pale yellow amorphous form.

IR (KBr) cm⁻¹ : 3420, 3020, 1350, 1150, 830, 590;

NMR(D₂ O) δppm: 2.49 (3H, s), 3.52 (4H, brs), 4.10 (2H, brd), 4.70 (2H,s), 6.1-6.3 (1H, m), 6.83 (1H, d, J=15.8 Hz), 7.34 (4H, s), 8.10 (1H, d,J=8.0 Hz), 8.6-8.8 (3H, m), 8.83 (1H, s), 8.95 (1H, d, J=7.0 Hz), 9.81(1H, s).

EXAMPLE 247N-[2-(4-chloro-N-methoxycarbonylmethylcinnamylamino)ethyl]-N-methyl-5-isoqunilinesulfonamide.2HCl

Yellow amorphous form.

IR (KBr)cm⁻¹ : 3420, 2620, 1750, 1350, 1140, 840, 590;

NMR(D₂ O)δppm: 3.07 (3H, s), 3.73 (4H, brt), 3.89 (3H, s), 4.2 (2H,brd), 4.37 (2H, s), 6.2-6.4 (1H, m), 6.89 (1H, d, J=16.0 Hz), 7.32 (4H,brq), 8.14 (1H, t, J=7.9 Hz), 8.6-8.8 (3H, m), 9.04 (1H, d, J=7.0 Hz),9.83 (1H, s).

EXAMPLE 248N-[2-(N-carbamoylmethyl-4-chlorocinnamylamino)-ethyl]-N-methyl-5-isoquinoline-sulfonamide.2HCl

Pale yellow amorphous form.

IR (KBr) cm⁻¹ : 3400, 1690, 1350, 1140, 830, 590;

NMR (D₂ O) δppm: 3.05 (3H, s), 3.5-3.8 (4H, m), 4.1-4.2 (2H, m), 4.23(2H, s), 6.2-6.4 (1H, m), 6.91 (1H, d, J=15.9 Hz), 734 (4H, brq), 8.11(1H, t, J=7.0 Hz), 8.6-8.8 (3H, m), 9.00 (1H, d, J=7.0 Hz), 9.80 (1H,s).

EXAMPLE 249N-[2-(4-chloro-N-cyanomethylcinnamylamino)ethyl)-N-methyl-5-isoquinolinesulfonamide.2HCl

Pale brown amorphous form.

IR (KBr)cm⁻¹ : 3420, 2570, 1350, 1140, 830, 590;

NMR (DMSO-d₆)δppm: 2.80 (2H, brt) 2.89 (3H, s), 3.3-3.5 (4H, m), 3.89(2H, s), 6.1- 6.3 (1H, m), 6.64 (1H, d, J=15.8 Hz), 7.43 (4H, brq), 8.09(1H, t, J=8.0 Hz), 8.63 (1H, d, J=7.6 Hz), 8.7-8.9 (3H, m), 9.98 (1H,s).

EXAMPLE 250N-[2-(4-chloro-N-methylcinnamylamino)ethyl]-N-morpholinocarbonylmethyl-5-isoquinolinesulfonamide

Colorless oil.

IR (KBr)cm⁻¹ : 1660, 1330, 1130;

NMR (D₂ O)δppm: 2.17 (3H, s), 2.57 (2H, t, J=6.3 Hz), 3.06 (2H, d, J=6.3Hz), 3.39 (4H, brs), 3.5-3.7 (6H, m), 4.41 (2H, s), 6.06 (1H, dt,J=15.9, 6.3 Hz), 6.40 (1H, d, J=15.9 Hz), 7.27 (4H, s), 7.66 (1H, t,J=8.0 Hz), 8.15 (1H, d. J=8.3 Hz), 8.43 (1H, d, J=6.4 Hz), 8.54 (1H, d,J=8.0 Hz), 8.66 (1H, d, J=6.4 Hz), 9.30 (1H, s).

EXAMPLE 251N-{2-[N-(2-aminoethyl)-4-chlorocinnamylamino]ethyl}-N-methyl-5-isoquinolinesulfonamide.3HCl

Colorless amorphous form.

IR (KBr)cm⁻¹ : 3420, 2950, 1490, 1350, 1140, 590;

NMR (D₂ O)δppm: 3.05 (3H, s) 3.5-3.8 (8H, m), 4.20 (2H, brd), 6.2-6.4(1H, m), 6.05 (1H, d, J=15.9 Hz), 7.37 (4H, brq), 8.16 (1H, t, J=7.9Hz), 8.6-8.8 (3H, m), 9.07 (1H, d, J=7.0 Hz), 9.84 (1H, s).

EXAMPLE 252N-[2-(4-chloro-N-methylcinnamylamino)ethyl]-N-[2-(1-pyperazinyl)ethyl]-5-isoquinolinesul-fonamide.4HCl

Colorless amorphous form.

IR (KBr)cm 3420, 2660, 1460, 1350, 1150, 590;

NMR (D₂ O)δppm: 3.04 (3H, s), 3.3-3.7 (12H, m), 3.8-4.1 (6H, m), 6.0-6.2(1H, m), 6.73 (1H, d, J=15.9 Hz), 7.18 (4H, s), 8.11 (1H, t, J=7.9 Hz),8.53 (1H, d, J=7.3 Hz), 8.6-8.8 (2H, m), 8.89 (1H, d, J=6.9 Hz), 9.78(1H, s).

EXAMPLE 253N-[2-(4-chloro-N-methylcinnamylamino)ethyl]-N-[2-(4-methyl-1-pyperazinyl)ethyl-5-isoquinolinesulfonamide.4HCl

Colorless amorphous form

IR (KBr)cm⁻¹ : 3420, 2660, 1460, 1140, 590;

NMR (D₂ O)δppm: 3.02 (3H, s), 3.3-3.7 (12H, m), 3.8-4.1(6H, m), 6.1-6.3(1H, m), 6.74 (1H, d, J=16.0 Hz), 7.19 (4H, s), 8.11 (1H, t, J=7.9 Hz),8.55 (1H, d, J=7.0 Hz), 8.6-8.8 (2H, m), 8.90 (1H, d, J=7.0 Hz), 9.79(1H, s).

EXAMPLE 254N-[2-(3-methyoxy-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl

Pale yellow crystalls.

Melting point 115°-118° C.;

IR (KBr)cm⁻¹ : 3420, 3200-2600, 1605, 1350, 1162, 1150;

NMR (DMSO-d₆)δppm: 1.40 (3H, d, J=6.4 Hz), 2.90-3.0 (2H, m), 3.15-3.25(2H, m), 3.78 (3H, s), 3.80-4.0 (1H, m), 6.22 (1H, dd, J=15.9, 8.8 Hz),6.70 (1H, d, J=15.9 Hz), 6.85-7.05 (3H, m), 7.30 (1H, t, J=7.9 Hz), 7.30(1H, br, disappears in D₂ O), 8.0 (1H, d, J=7.9 Hz), 8.04 (1H, d, J=7.3Hz), 8.59 (1H, d, J=7.3 Hz), 8.68 (1H, d, J=7.9 Hz), 8.82 (2H, s), 8.91(1H, m, disappears in D₂ O), 9.60 (2H, br, disappears in D₂ O), 9.88(1H, s).

EXAMPLE 255 N-[ 2-(4-hydroxymethyl-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

IR (KBr)cm⁻¹ : 1620, 1326, 1160, 1139, 831, 761, 598;

NMR(CDCl₃)δppm: 1.07 (3H, d, J=6,35 Hz), near 1.95 (3H, br), 2.60 (2H,t. J=6.0 Hz), 2.96 (2H, m), 3.05 (1H, m), 4.68 (2H, s), 5.78 (1H, dd,J=15.87, 7.82 Hz), 6.27 (1H, d, J=8.30 Hz), 7.67 (1H, dd, J=8.30, 7.32Hz), 8.18 (1H, d, J=8.30 Hz), 8.40 (1H, d, J=6.11 Hz), 8.44 (1H, d,J=7.32 Hz), 8.61 (1H, d, J=6.11 Hz), 9.32 (1H, s).

EXAMPLE 256N-[2-(α-methyl-4-methylthiocinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form.

IR (KBr)cm⁻¹ : 1618, 1493, 1324, 1160, 1138, 1094, 830, 807, 760, 598;

NMR (CDCl₃)δppm: 105 (3H, d, J=6.35 Hz), 2.48 (3H, s), 2.60 (2H, m),2.96 (2H, t, J=6.10 Hz), 3.03 (1H, m), 5.75 (1H, dd, J=15.87, 7.81 Hz),6.22 (1H, d, J - 15.87 Hz), 7.18 (4H, s), 7.67 (1H, dd, J=8.30, 7.32Hz), 8.17 (1H, d, J=8.30 Hz), 8.43 (1H, d, J=6.10 Hz), 8.44 (1H, d,J=7.32 Hz), 8.68 (1H, d, J=6.10 Hz), 9.34 (1H, s).

EXAMPLE 257N-[2-(α-methyl-4-methylsulfinylcinnamylamino)ethyl-5-isoquinolinesulfonamide

Colorless amorphous form.

IR (KBr)cm⁻¹ ; 1618, 1326, 1160, 1138, 1089, 1041, 831, 762, 599;

NMR(CDCl₃)δppm: 1.11 (3H, d, J=6.59 Hz), 2.0-4.0 (2H, br), 2.65 (2H, m),2.73 (3H, s), 3.00 (2H, t, J=5.62 Hz), 3.15 (1H, m), 5.96 (1H, dd,J=16.11, 7.81 Hz), 6.36 (1H, d, J=16.11 Hz), 7.42 (2H, d, J=8.30 Hz),7.58 (2H, d, J=8.30 HZ), 7.68 (1H, dd, J=8.31, 7.32 Hz), 8.10 (1H, d,J=8.30 Hz), 7.68 (1H, dd, J=8.31, 7.32 Hz), 8.19 (1H, d, J=8.31 Hz),8.44 (1H, d, J=6.1 Hz), 8.44 (1H, d, J=7.32 Hz), 8.67 (1H, d, J=6.10Hz), 9.35 (1H, s).

EXAMPLE 258N-[2-(α-methyl-4-methylsulfonyalcvnnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous.

IR (KBr)cm⁻¹ ; 1310, 1149, 1090, 960, 832, 765, 599, 542;

NMR (CDCl₃)δppm: 1.09 (3H, d, J=6.35 Hz), 2.62 (2H, m), 2.98 (2H, t,J=5.62 Hz), 3.05 (3H, s), 3.10 (1H, m), 6.02 (1H, dd, J=15.87, 7.57 Hz),6.37 (1H, d, J=15.87 Hz), 3.05 (3H, s), 3.10 (1H, m), 6.02 (1H, dd,J=15,87, 7,57 Hz), 6.37 (1H, d, J=15.87 Hz), 7.44 (2H, d, J=8.30 Hz),7.69 (1H, dd, J=8.06, 7.57 Hz), 7.85 (2H, d, J=8.30 Hz), 8.20 (1H, d,J=8.06.Hz), 8.44 (1H, d, J=6.35 Hz), 8.45 (1H, d, J=7.57 Hz), 8.67 (1H,d, J=6.35 Hz), 9.36 (1H, s).

EXAMPLE 259N-[2-(4-cyano-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless needles.

Melting point: 62°-65° C.;

IR (KBr)cm⁻¹ :; 2230, 1620, 1322, 1140, 600;

NMR (CDCl₃)δppm: 1.08 (3H, d, J=6.3 Hz), 2.57-2.65 (2H, m), 2.9-3.0 (2H,m), 3.0-3.2 (1H, m), 5.98 (1H, dd, J=15.9, 7.8 Hz), 6,33 (1H, d, J=15.9Hz), 7.36 (2H, d, J=8.3 Hz), 7.58 (2H, d, J=8.3 Hz), 7.69 (1H, t, J=8.0Hz), 8.20 (1H, d, J=8.0 Hz), 8.40-8.50 (2H, m), 8.69 (1H, d, J=6.1 Hz),9.36 (1H, s).

EXAMPLE 260N-[2-(4-carbamoyl-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Color-less needles

Melting point: 66°-70° C.;

IR (KBr)cm⁻¹ :; 3450, 1662, 1610, 1320, 1160, 1140;

NMR (CDCl₃)δppm; 1.08 (3H, d, J=6.4 HZ), 2.61 (2H, M), 2.90-3.20 (3H,m), 5.93 (1H, dd, J=16.1, 7.8 Hz), 6.32 (1H, d, J=16.1 Hz), 7.32 (2H, d,J=8.3 Hz), 7.66 (1H, t, J=8.3 Hz), 7.74 (2H, d, J=8.3 Hz), 8.18 (1H, d,J=8.3 Hz), 7.74 (2H, d, J=8.3 Hz), 8.18 (1H, d, J=8.3 Hz), 8.40-8.50(2H, m), 8.67 (1H, d, J=6.1 Hz), 9.34 (1H, s).

EXAMPLE 261N-2-(4-acetamide-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form.

IR (KBr)cm⁻¹ ; 3300-2800, 1670, 1600, 1538, 1320, 1160, 1140;

NMR (CDCl₃)δppm; 1.03 (3H, d, J=6.6 Hz), 2.16 (3H, s), 2.55-2.65 (2H,m), 2.90-3.10 (3H, m), 5.68 (1H, dd, J=15.9, 8.1 Hz), 6.20 (1H, d,J=15.9 Hz), 7.17 (2H, d, J=8.5 Hz), 7.44 (2H, d, J=8.5 Hz), 7.66 (1H,dd, J=8.3, 7.3 Hz), 8.44 (1H, d, J=7.3 Hz), 7.66 (1H, s, disappears inD₂ O), 8.16 (1H, d, J=8.3 Hz), 8.44 (1H, d, J=7.3 Hz), 8.44 (1H, d,J=6.1 Hz), 8.61 (1H, d, J=6.1 Hz), 9.31 (1H, s).

EXAMPLE 262N-[2-(3-nitro-3-methoxy-α-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide.HCl

Colorless crystals.

Melting point: 159°-163° C.;

IR (KBr) cm⁻¹ :; 3450, 3150-2600, 1530, 1330, 116-1140;

NMR (DMSO-d₆)δppm: 1.34 (3H, d, J=6.6 Hz), 2.75-3.0 (2H, m), 3.02-3.20(2H, m}, 3.90 (3H, s), 3.90-4.10 (1H, m), 6.30 (1H, dd, J=15.6, 8.6 Hz),6.57 (1H, d, J=15.6 Hz), 7.26 (1H, d, J=7.8 Hz), 7.32 (1H, d, J=7.8 Hz),7.83 (1H, t, J=7.8 Hz), 8.35-8.45 (3H, m), 8.52 (1H, brs, disappears inD₂ O), 8.7 (1H, d, J=6.1 Hz), 9.25 (2H, brs, disappears in D₂ O), 9.47(1H, s).

EXAMPLE 263N-[2-(2-methoxy-α-methylcinnamylamino)-ethyl]-5-isoquinolinesulfonamide

Colorless amorphous form.

IR (KBr) cm⁻¹ : 1490, 1463, 1326, 1244, 1160, 1138, 755, 599;

NMR (CDCl₃) δppm: 1.05 (3H, d, J=6.35 Hz), 2.6 (2H, m), 2.96 (2H, t,J=5.62 Hz), 3.04 (1H, m), 3.82 (3H, s), 5.79 (1H, dd, J=16.12, 7.94 Hz),6.85 (1H, brd, J=8.06 Hz), 6.90 (1H, brt, J=7.57 HZ), 7.21 (1H, m), 7.31(1H, dd, J=16.12, 7.94 Hz), 6.85 (1H, brd, J=8.06 Hz), 6.90 (1H, brt,J=7.57 Hz), 7.21 (1H, m) 7.31 (1H, dd, J=7.57, (1.71 Hz), 7.66 (1H, dd,J=8.06, 7.57 Hz), 8.16 (1H, t, J=8.06 Hz), 8.44 (2H, m), 8.67 (1H, d,J=6.35 Hz), 9.33 (1H, s).

EXAMPLE 264

To confirm the usefulness of the above-mentioned compound of the presentinvention, the following experiments were carried out.

Vessel Smooth Muscle Relaxation Action (V.R. ED₅₀).

A rabbit was killed by bleeding and the superior mesenteric artery wasremoved and cut to a spiral form to prepare a band-shaped specimenaccording to a conventional method. The specimen was suspended byloading a strain in Krebs-Henseleit solution through which an oxygen gascontaining 5% carbon dioxide was bubbled. The specimen was contracted byadding potassium chloride to maintain a predetermined strain.Thereafter, a test compound was cumulatively administrated. Therelaxation activity of the test compound was expressed by ED₅₀ (μM),i.e., a concentration of the compound which relaxes the strain to 50% ofthe strain only in the presence of potassium chloride (as 100%)

Platelet Agglutination Inhibition (P.A.; IC₅₀)

(1) Preparation of washed platelets

The blood was obtained from a healthy person and mixed with one tenthvolume of 0.38% sodium citrate, and the mixture was centrifuged at 700×Gfor 10 minutes to obtain a platelet-rich plasma (PRP). To the PRP wasadded one sixth volume of ACD solution (2.2% sodium citrate, 0.8% citricacid and 2.2% glucose; freshly prepared before use) and the mixture wascentrifuged at 1500×G for 10 minutes to obtain a platelet pellet. Next,the platelet pellet was suspended in a modified HEPES-Tyrode solution(135 mM NaCl, 2.7 mM KCl, 1 mM MgCl₂, 0.1 mg/ml glucose, 20 mM HEPES; pH7.4). To this suspension was added one sixth volume of ACD solution, andthe whole was further centrifuged at 1500×G for 5 minutes to prepare aplatelet pellet. The platelet pellet was then suspended in a modifiedHEPES Tyrode solution to obtain about 3×10⁵ /μl in washed plateletsuspension.

(2) Measurement of platelet agglutination

To 270 μl of the washed platelet suspension was added 3 μl of a solutionof a test compound dissolved in an appropriate medium in differentconcentration, and the mixture was pre-incubated at 37° C. for 2minutes. After an addition of 30 μl of 20 μg/ml collagen solution, theabsorbance was measured with 4-channel agglutination analyzer (HEMATracer 601; Niko Bioscience).

(3) Determination of effect of test compounds

As a control, the above-mentioned procedure was carried out except thatthe test medium without a test compound was used, and the absorbancebefore addition of collagen and the maximum absorbance after addition ofcollagen were measured, and the difference between both absorbances wastaken as 100% agglutination.

For test compound, the absorbance before an addition of collagen and themaximum absorbance after an addition of collagen were measured, and apercent of the inhibition was determined, compared with the control. Aconcentration of test compound which provides 50% of the inhibitionexpressed as IC₅₀.

Calmodulin-Dependent Phosphodiesterase Inhibition

(1) Preparation of Calmodulin-Dependent

Phosphodiesterase

(Ca²⁺ PDE)Ca²⁺ PDE was partially purified from the brain of rat byDEAE-Sepharose column chromatography.

(2) Preparation of calmodulin

Calmodulin was purified from the calf brain using a calmodulin inhibitorW-7 affinity column.

(3) Measurement of Ca²⁺ PDE activity

A reaction mixture contained 20 μl of 500 mM Tris-HCl (pH 8.0), 20 μl of50 mM MgCl₂, 20 μl of 2 mM CaCl₂ (or 10 mM EGTA), 20 μl of 1 mg/mlbovine serum albumin, PDE, 200 mg of calmodulin, test sample anddistilled water to make total volume 200 μl. To the mixture was added 20μl of 4 μM [³ H]-cGMP (2.5 μCi/ml), the mixture was incubated at 30° C.for 15 minutes, and then heated in boiling water for 3 to 5 minutes toterminate the reaction, and cooled in ice-water bath. 20 μg of5'-nucleotidase (Snake venum) was added to the mixture, and the mixturewas again incubated at 30° C. for 10 minutes. After addition of about 2ml of water, the sample was applied to a cation exchange resin column(Biorad AG.AG50W-X4 to adsorbe the [³ H]-guanosine and additionallyabout 2 ml of washing water for the sample was added to the column. Thecolumn was washed with about 20 ml of water, and the adsorbed [³H]-guanosine was eluted with 3 ml of 3N NH₄ OH, and the elute wasdirectly received by a vial. After an addition of 10 ml of an emulsifiedscintillation solution (ACS-II, AMERSHAM) the radio activity wasmeasured by a scintillation counter LS7500 (Beckmann). The enzymeactivity in the presence of calmodulin was taken as 0%, and aconcentration of a test compound in μM which provides a 50% inhibitionwas expressed as IC₅₀.

The results are set forth in the following Table.

    ______________________________________                                        Example             P.A. (IC.sub.50)                                                                         Ca.sup.2+ PDE(IC.sub.50)                       No.     V.R. (ED.sub.50)                                                                          (μM)    (μM)                                        ______________________________________                                         1                                                                             2      47                                                                     3                                                                             4      12                     53                                              5                                                                             6                                                                             7      1.6                    13                                              8      1.8                    51                                              9                                                                             10     6.4                    37                                              11                            59                                              12                                                                            13     1.2                    15                                              14                                                                            15                            43                                              16                                                                            17                                                                            18                                                                            19     22                     20                                              20     1                      23                                              21                                                                            22     1.8                                                                    23     0.25                   66                                              24     8.3                    63                                              25     0.55                   70                                              26                 10                                                         27                                                                            28                                                                            29     7.6         73                                                         30                                                                            31     24 ± 7.0                                                            32                                                                            33     21                                                                     34     1.8                                                                    35     6.9                                                                    36     0.81                   10.5                                            37     4.4                    29                                              38     8.1                                                                    39                                                                            40                   4.7                                                      41     1.8         10                                                         42     6.2                                                                    43     0.36                   3.8                                             44                                                                            45     7.5                                                                    46     4                      36                                              47     0.39                   18                                              48     3.9                    6.5                                             49     0.92                                                                   50     0.67        70         11                                              51     0.17                   38                                              52     9.9                                                                    53     1.3                                                                    54     1.7                                                                    55     8.6                                                                    56     1.2                    39                                              57     0.75                   50                                              58     0.25                   63                                              59                                                                            60                 10                                                         61                 10                                                         62     23                                                                     63                                                                            64                                                                            65                                                                            66                                                                            67     2.2                    3.6                                             68     3.3 ± 1.4                                                                               6                                                         69     14                                                                     70                                                                            71     14          93                                                         72     4                      6.2                                             73     14                     21                                              74                   2.8                                                      75     9.7                                                                    76     2.9                                                                    77     1.4                                                                    78     1.8                                                                    79     5.5                                                                    80     2.4                    13                                              81     1.7                    32                                              82     0.86                   33                                              83     0.39                   24                                              84     43                                                                     85                            75                                              86     13                     24                                              87     1.7                    1.9                                             88     4.3                    14                                              89                                                                            90     0.33                   3.4                                             91     1.1                    10                                              92                            63                                              93     0.31                   3.4                                             94                                                                            95                                                                            96                                                                            97                 39                                                         98     22                                                                     99     2.8                    61                                             100     95                                                                    101     29                                                                    102     24                                                                    103                                                                           104                                                                           105     5.4                    12                                             106     8.9                    28                                             107                                                                           108     1.2                    10                                             109     0.59                   1.3                                            110     3.8                    9.3                                            111     7.0                    77                                             112                                                                           113     0.88        20         1.2                                            114     54          100                                                       115                                                                           116     1.5                                                                   117                                                                           118                                                                           119     11                     51                                             120     19 ± 3.0                                                           121                                                                           122                                                                           123     4.8         22                                                        124     11                                                                    125     9.2                                                                   126                 10                                                        127                 39                                                        128     1.8                                                                   129     0.82                                                                  130     13                                                                    131     1.5                                                                   132                                                                           133                                                                           134                                                                           135                                                                           136                                                                           137                                                                           138                                                                           139                                                                           140                                                                           141                                                                           142     6.8                    1.1                                            143     0.82                   1.5                                            144     1.8                    1.0                                            145                 12                                                        146     2.8                                                                   147     1.2                    42                                             148                                                                           149                                                                           150                                                                           151                                                                           152                                                                           153     1.5         25                                                        154                 60                                                        155     41          55                                                        156     4.4         19         19                                             157     3.2         36         8.6                                            158     17                     21                                             159     5.1         24         92                                             160     1.8         56                                                        161     4.7                                                                   162     35                                                                    163     31                                                                    164     4.1                                                                   165     11                                                                    166     1.4         90                                                        167     1.2         52                                                        168     3.6         26                                                        169     4.6                                                                   170     5.2                                                                   171     5.4                                                                   172     1.0         51         9.4                                            173                                                                           174     11                                                                    175     2.0                    13                                             176     1.2         55         8.5                                            177     2.7         56         24                                             178     2.4                    50                                             179     2.8         51         7.8                                            180     1.8                    4.8                                            181     8.4         38         4.7                                            182     17                                                                    183     2.8                                                                   184     2.8                    12                                             185     0.21                                                                  186                                                                           187                                                                           188     4                                                                       189-I 0.22                   2.7                                              189-II                                                                              0.20                                                                     189-III                                                                            0.29                   1.0                                            190     0.19                                                                  191     1.9                    26                                             192     0.12                   84                                             193     3.2                    12                                             194                            80                                             195                                                                           196                                                                           197                                                                           198                                                                           199                                                                           200                                                                           201     3.2                                                                   202     1.3                                                                   203                                                                           204                                                                           205                                                                           206                                                                           207                                                                           208                                                                           209                                                                           210                                                                           211                                                                           212                                                                           213                                                                           214                                                                           215                                                                           216                                                                           ______________________________________                                    

It was shown that other compounds of the present inventions describedabove have a platelet agglutination-inhibitory action as well as aninhibitory action against protein kinase A, myosin light chain kinase,protein kinase C, calmodulin-dependent protein kinase II, cyclic AMPdependent phosphodiesterase and the like, but have little effect oncardiac functions.

As seen from the above-mentioned results, the present compound a asdescribed above have a smooth muscle relaxation action, and therefore,are useful as vasodilator or brain circulation-improving agents; andsince the present compound have a platelet agglutination-inhibitoryaction, they are useful as prophylactic or therapeutic agents forthrombosis Moreover, since the present compounds have an inhibitoryactivity against various kinases, they are useful as anti-tumer agents.The above-mentioned compounds have a low toxicity, and therefore, areapplicable as pharmaceutical preparations.

We claim:
 1. A compound represented by the formula (I_(a)): ##STR29##wherein when Y is a nitrogen atom,R₁ represents a hydrogen atom, methyl,tolylmethyl or 3,4-dichlorobenzyl; R₁₀ is selected from the groupconsisting of a hydrogen atom, hydroxy, methoxy, acetoxy,isoquinolylsulfonyloxy, benzyloxy and pyridylmethoxy; R₁₁ is a hydrogenatom or benzyloxy; and when n represents an integer of 2,A is a grouprepresented by the formula: ##STR30## wherein R₁₄ is selected from thegroup consisting of hydroxy, acetoxy, phenyl, tolylmethoxy,3,4-dichlorobenzyloxy, benzylamino, an amino disubstituted with methyland 3,4-dichlorobenzyl, 3,4-dichlorobenzylamino and an aminodisubstituted with methyl and benzyl; R₁₅ is a hydrogen atom, ortogether with R₁₄ form an ethylenedioxy group or an oxo group; and R₁₂and R₁₃ are hydrogen atom; or when n represents an integer of 3A is agroup represented by the formula: >N--R₁₆ wherein R₁₆ is selected fromthe group consisting of a hydrogen atom, phenyl, benzyloxycarbonyl,benzylcarbonyl, phenthycarbonyl and phenylpropyl; and R₁₂ and R₁₃ arehydrogen atom, or together form a oxo group; or when Y is a carbonatom,R₁ is methyl; R₁₀ is hydroxy or naphthylsulfonyloxy; R₁₁ is ahydrogen atom; R₁₂ and R₁₃ are hydrogen atom; n is an integer of 2; andA is >N-phenyl or >N--COOCH₂ -phenyl;and quarternary ammonium salts, orsalts of the compound of the formula (Ia).